Professional Education

  • PhD, Harvard University, Neurobiology (1999)
  • AB, Vassar College, Biology (1993)

Research & Scholarship

Current Research and Scholarly Interests

Dr. Zeitzer is a circadian physiologist specializing in the understanding of the impact of light on circadian rhythms and other aspects of non-image forming light perception.
He examines the manner in which humans respond to light and ways to manipulate this responsiveness, with direct application to jet lag, shift work, and altered sleep timing in teens. Dr. Zeitzer has also pioneered the use of actigraphy in the determination of epiphenomenal markers of psychiatric disorders.

Clinical Trials

  • Efficacy and Safety of Tasimelteon Compared With Placebo in Totally Blind Subjects With Non-24-Hour Sleep-Wake Disorder Recruiting

    The purpose of this study is to evaluate the efficacy and safety of a six month double-mask treatment of tasimelteon or placebo in male and female subjects with Non-24-Hour Sleep-Wake Disorder

    View full details

  • Light Flashes to Treat Delayed Sleep Phase Disorder (DSPD) Not Recruiting

    Delayed Sleep Phase Disorder (DSPD) is a sleep disruption that commonly occurs in teens and manifests as a difficulty in waking up in the morning, going to sleep early enough at night, and daytime disturbances such as depression, fatigue, and restlessness. The purpose of this study is to determine if brief flashes of light, that are scheduled to occur during sleep, are effective in treating DSPD.

    Stanford is currently not accepting patients for this trial. For more information, please contact Jamie Zeitzer, PhD, 650-493-5000 Ext. 62410.

    View full details

  • Acupuncture for Sleep Disruption in Cancer Survivors Not Recruiting

    The proposed study will recruit 60 women with breast cancer who finished undergoing treatment who complain of persistent insomnia problems that began with onset of their cancer diagnosis. The eligible women would be randomized and stratified by sleep problems to two arms: (Acupuncture Arm vs. Sham Acupuncture) with a goal of having 48 patients complete the study (we anticipate about 20% attrition rate). The study interventions will begin after patients completed their treatment. The placebo control for acupuncture will be a validated sham acupuncture control Assessments will be made with daily diaries and with weekly questionnaires. PSG data will be collected on the subsample of the population. Data will be gathered via pencil-and-paper measures before, during, immediately following, one month following the completion of treatment and six months after the conclusion of treatment. In addition, actigraphy data (objective sleep continuity data) will be acquired prior to and following treatment

    Stanford is currently not accepting patients for this trial. For more information, please contact David Spiegel, (650) 723 - 6421.

    View full details

  • Bright Light as a Countermeasure for Circadian Desynchrony Recruiting

    Light is the primary means by which the internal circadian clock remains aligned ("entrained") with the external world. Misalignment of this internal clock can occur during situations such as shift work and jet travel across multiple time zones (jet lag). The purpose of this study is to examine the parameters of light and how they affect entrainment of the clock.

    View full details

  • Examination of the Effectiveness of Suvorexant in Improving Daytime Sleep in Shift Workers Recruiting

    The purpose of this study is to test the hypothesis that ingestion of the wake-inhibiting drug suvorexant 30 minutes prior to daytime sleep initiation in individuals working overnight shifts will significantly improve both objective (total sleep time, sleep efficiency, wake after sleep onset) and subjective (sleep quality) measures of daytime sleep.

    View full details

  • Toileting at Night in Older Adults: Light to Maximize Balance, Minimize Insomnia Not Recruiting

    To examine the change in balance that occurs in older individuals when exposed to different colored lights at night.

    Stanford is currently not accepting patients for this trial. For more information, please contact Jamie M Zeitzer, PhD, 650-493-5000 Ext. 62410.

    View full details


2017-18 Courses

Stanford Advisees

Graduate and Fellowship Programs


All Publications

  • When is a proxy not a proxy? The foibles of studying non-image forming light. The Journal of physiology Zeitzer, J. M. 2018; 596 (11): 2029–30

    View details for DOI 10.1113/JP276076

    View details for PubMedID 29717490

  • Serotonin transporter polymorphism, depressive symptoms, and emotional impulsivity among advanced breast cancer patients SUPPORTIVE CARE IN CANCER Kim, Y., Carver, C. S., Hallmayer, J. F., Zeitzer, J. M., Palesh, O., Neri, E., Nouriani, B., Spiegel, D. 2018; 26 (4): 1181–88


    This study tested a theory linking a marker of low serotonergic function to both depression and impulsivity in a sample of advanced breast cancer patients, among whom elevated depressive symptoms and difficulty regulating emotions are commonly reported.A total of 95 patients provided blood samples for serotonin transporter polymorphic region of the gene (5-HTTLPR) and completed questionnaires that measured depressive symptoms and emotional impulsivity.Structural equation modeling revealed that the s allele of 5-HTTLPR was related to greater depressive symptoms (β = .20, p < .042) but only marginally to greater emotional impulsivity (β = .19, p < .068). Depressive symptoms and emotional impulsivity were positively related (β = .33, p < .003). Further tests explored possible mediation from genotype to one psychological variable via the other. Results suggest that depressive symptoms, particularly perceived interpersonal rejection, may be a pathway linking genotype to emotional impulsivity.Findings provide the first evidence that low serotonergic function contributes to both depression and impulsivity within a clinically meaningful sample. Furthermore, the link of s allele of 5-HTTLPR to emotional impulsivity was mediated by depressive symptoms, particularly perceptions of social rejection. Findings have implications for advanced breast cancer patients' treatment decision.

    View details for DOI 10.1007/s00520-017-3940-0

    View details for Web of Science ID 000425743100018

    View details for PubMedID 29090386

  • THE EFFECTS OF CBT-I ON COGNITIVE FUNCTIONING IN INDIVIDUALS WITH INSOMNIA AND MILD COGNITIVE IMPAIRMENT Goldstein-Piekarski, A. N., O'Hora, K., Buchanan, A., Lee, C., Hernandez, B., Zeitzer, J. M., Friedman, L., Kushida, C., Yesavage, J. OXFORD UNIV PRESS INC. 2018: A154–A155
  • The association between mood state and chronobiological characteristics in bipolar I disorder: a naturalistic, variable cluster analysis-based study INTERNATIONAL JOURNAL OF BIPOLAR DISORDERS Gonzalez, R., Suppes, T., Zeitzer, J., McClung, C., Tamminga, C., Tohen, M., Forero, A., Dwivedi, A., Alvarado, A. 2018; 6: 5


    Multiple types of chronobiological disturbances have been reported in bipolar disorder, including characteristics associated with general activity levels, sleep, and rhythmicity. Previous studies have focused on examining the individual relationships between affective state and chronobiological characteristics. The aim of this study was to conduct a variable cluster analysis in order to ascertain how mood states are associated with chronobiological traits in bipolar I disorder (BDI). We hypothesized that manic symptomatology would be associated with disturbances of rhythm.Variable cluster analysis identified five chronobiological clusters in 105 BDI subjects. Cluster 1, comprising subjective sleep quality was associated with both mania and depression. Cluster 2, which comprised variables describing the degree of rhythmicity, was associated with mania. Significant associations between mood state and cluster analysis-identified chronobiological variables were noted. Disturbances of mood were associated with subjectively assessed sleep disturbances as opposed to objectively determined, actigraphy-based sleep variables. No associations with general activity variables were noted. Relationships between gender and medication classes in use and cluster analysis-identified chronobiological characteristics were noted. Exploratory analyses noted that medication class had a larger impact on these relationships than the number of psychiatric medications in use.In a BDI sample, variable cluster analysis was able to group related chronobiological variables. The results support our primary hypothesis that mood state, particularly mania, is associated with chronobiological disturbances. Further research is required in order to define these relationships and to determine the directionality of the associations between mood state and chronobiological characteristics.

    View details for DOI 10.1186/s40345-017-0113-5

    View details for Web of Science ID 000425390600001

    View details for PubMedID 29457195

  • Subjective versus objective evening chronotypes in bipolar disorder Journal of Affective Disorders Gershon, A., Kaufmann, C. N., Depp, C. A., Miller, S., Do, D., Zeitzer, J. M., Ketter, T. A. 2018; 225: 342–349


    Disturbed sleep timing is common in bipolar disorder (BD). However, most research is based upon self-reports. We examined relationships between subjective versus objective assessments of sleep timing in BD patients versus controls.We studied 61 individuals with bipolar I or II disorder and 61 healthy controls. Structured clinical interviews assessed psychiatric diagnoses, and clinician-administered scales assessed current mood symptom severity. For subjective chronotype, we used the Composite Scale of Morningness (CSM) questionnaire, using original and modified (1, ¾, ⅔, and ½ SD below mean CSM score) thresholds to define evening chronotype. Objective chronotype was calculated as the percentage of nights (50%, 66.7%, 75%, or 90% of all nights) with sleep interval midpoints at or before (non-evening chronotype) vs. after (evening chronotype) 04:15:00 (4:15:00a.m.), based on 25-50 days of continuous actigraph data.BD participants and controls differed significantly with respect to CSM mean scores and CSM evening chronotypes using modified, but not original, thresholds. Groups also differed significantly with respect to chronotype based on sleep interval midpoint means, and based on the threshold of 75% of sleep intervals with midpoints after 04:15:00. Subjective and objective chronotypes correlated significantly with one another. Twenty-one consecutive intervals were needed to yield an evening chronotype classification match of ≥ 95% with that made using the 75% of sleep intervals threshold.Limited sample size/generalizability.Subjective and objective chronotype measurements were correlated with one another in participants with BD. Using population-specific thresholds, participants with BD had a later chronotype than controls.

    View details for DOI 10.1016/j.jad.2017.08.055

    View details for PubMedCentralID PMC5626649

  • Correlates of sleep quality in midlife and beyond: a machine learning analysis. Sleep medicine Kaplan, K. A., Hardas, P. P., Redline, S., Zeitzer, J. M. 2017; 34: 162-167


    In older adults, traditional metrics derived from polysomnography (PSG) are not well correlated with subjective sleep quality. Little is known about whether the association between PSG and subjective sleep quality changes with age, or whether quantitative electroencephalography (qEEG) is associated with sleep quality. Therefore, we examined the relationship between subjective sleep quality and objective sleep characteristics (standard PSG and qEEG) across middle to older adulthood.Using cross-sectional analyses of 3173 community-dwelling men and women aged between 39 and 90 participating in the Sleep Heart Health Study, we examined the relationship between a morning rating of the prior night's sleep quality (sleep depth and restfulness) and polysomnographic, and qEEG descriptors of that single night of sleep, along with clinical and demographic measures. Multivariable models were constructed using two machine learning methods, namely lasso penalized regressions and random forests.Little variance was explained across models. Greater objective sleep efficiency, reduced wake after sleep onset, and fewer sleep-to-wake stage transitions were each associated with higher sleep quality; qEEG variables contributed little explanatory power. The oldest adults reported the highest sleep quality even as objective sleep deteriorated such that they would rate their sleep better, given the same level of sleep efficiency. Despite this, there were no major differences in the predictors of subjective sleep across the age span.Standard metrics derived from PSG, including qEEG, contribute little to explaining subjective sleep quality in middle-aged to older adults. The objective correlates of subjective sleep quality do not appear to systematically change with age despite a change in the relationship between subjective sleep quality and objective sleep efficiency.

    View details for DOI 10.1016/j.sleep.2017.03.004

    View details for PubMedID 28522086

  • Daily Patterns of Accelerometer Activity Predict Changes in Sleep, Cognition, and Mortality in Older Men. journals of gerontology. Series A, Biological sciences and medical sciences Zeitzer, J. M., Blackwell, T., Hoffman, A. R., Cummings, S., Ancoli-Israel, S., Stone, K. 2017


    There is growing interest in the area of "wearable tech" and its relationship to health. A common element of many of these devices is a triaxial accelerometer that can yield continuous information on gross motor activity levels; how such data might predict changes in health is less clear.We examined accelerometry data from 2,976 older men who were part of the Osteoporotic Fractures in Men (MrOS) study. Using a shape-naive technique, functional principal component analysis, we examined the patterns of motor activity over the course of 4-7 days and determined whether these patterns were associated with changes in polysomnographic-determined sleep and cognitive function (Trail Making Test-Part B [Trails B], Modified Mini-Mental State Examination [3MS]), as well as mortality over 6.5-8 years of follow-up.In comparing baseline to 6.5 years later, multivariate modeling indicated that low daytime activity at baseline was associated with worsening of sleep efficiency (p < .05), more wake after sleep onset (p < .05), and a decrease in cognition (Trails B; p < .001), as well as a 1.6-fold higher rate of all-cause mortality (hazard ratio = 1.64 [1.34-2.00]). Earlier wake and bed times were associated with a decrease in cognition (3MS; p < .05). Having a late afternoon peak in activity was associated with a 1.4-fold higher rate of all-cause mortality (hazard ratio = 1.46 [1.21-1.77]). Those having a longer duration of their daytime activity with a bimodal activity pattern also had over a 1.4-fold higher rate of cardiovascular-related mortality (hazard ratio = 1.42 [1.02-1.98]).Patterns of daily activity may be useful as predictive biomarkers for changes in clinically relevant outcomes, including mortality and changes in sleep and cognition in older men.

    View details for DOI 10.1093/gerona/glw250

    View details for PubMedID 28158467

  • When a gold standard isn't so golden: Lack of prediction of subjective sleep quality from sleep polysomnography. Biological psychology Kaplan, K. A., Hirshman, J., Hernandez, B., Stefanick, M. L., Hoffman, A. R., Redline, S., Ancoli-Israel, S., Stone, K., Friedman, L., Zeitzer, J. M. 2017; 123: 37-46


    Reports of subjective sleep quality are frequently collected in research and clinical practice. It is unclear, however, how well polysomnographic measures of sleep correlate with subjective reports of prior-night sleep quality in elderly men and women. Furthermore, the relative importance of various polysomnographic, demographic and clinical characteristics in predicting subjective sleep quality is not known. We sought to determine the correlates of subjective sleep quality in older adults using more recently developed machine learning algorithms that are suitable for selecting and ranking important variables.Community-dwelling older men (n=1024) and women (n=459), a subset of those participating in the Osteoporotic Fractures in Men study and the Study of Osteoporotic Fractures study, respectively, completed a single night of at-home polysomnographic recording of sleep followed by a set of morning questions concerning the prior night's sleep quality. Questionnaires concerning demographics and psychological characteristics were also collected prior to the overnight recording and entered into multivariable models. Two machine learning algorithms, lasso penalized regression and random forests, determined variable selection and the ordering of variable importance separately for men and women.Thirty-eight sleep, demographic and clinical correlates of sleep quality were considered. Together, these multivariable models explained only 11-17% of the variance in predicting subjective sleep quality. Objective sleep efficiency emerged as the strongest correlate of subjective sleep quality across all models, and across both sexes. Greater total sleep time and sleep stage transitions were also significant objective correlates of subjective sleep quality. The amount of slow wave sleep obtained was not determined to be important.Overall, the commonly obtained measures of polysomnographically-defined sleep contributed little to subjective ratings of prior-night sleep quality. Though they explained relatively little of the variance, sleep efficiency, total sleep time and sleep stage transitions were among the most important objective correlates.

    View details for DOI 10.1016/j.biopsycho.2016.11.010

    View details for PubMedID 27889439

    View details for PubMedCentralID PMC5292065

  • Anatomy and Physiology of the Circadian System SLEEP AND NEUROLOGIC DISEASE Najjar, R. P., Zeitzer, J. M., Miglis, M. G. 2017: 29–53
  • Aberrant nocturnal cortisol and disease progression in women with breast cancer BREAST CANCER RESEARCH AND TREATMENT Zeitzer, J. M., Nouriani, B., Rissling, M. B., Sledge, G. W., Kaplan, K. A., Aasly, L., Palesh, O., Jo, B., Neri, E., Dhabhar, F. S., Spiegel, D. 2016; 158 (1): 43-50


    While a relationship between disruption of circadian rhythms and the progression of cancer has been hypothesized in field and epidemiologic studies, it has never been unequivocally demonstrated. We determined the circadian rhythm of cortisol and sleep in women with advanced breast cancer (ABC) under the conditions necessary to allow for the precise measurement of these variables. Women with ABC (n = 97) and age-matched controls (n = 24) took part in a 24-h intensive physiological monitoring study involving polysomnographic sleep measures and high-density plasma sampling. Sleep was scored using both standard clinical metrics and power spectral analysis. Three-harmonic regression analysis and functional data analysis were used to assess the 24-h and sleep-associated patterns of plasma cortisol, respectively. The circadian pattern of plasma cortisol as described by its timing, timing relative to sleep, or amplitude was indistinguishable between women with ABC and age-matched controls (p's > 0.11, t-tests). There was, however, an aberrant spike of cortisol during the sleep of a subset of women, during which there was an eightfold increase in the amount of objectively measured wake time (p < 0.004, Wilcoxon Signed-Rank). This cortisol aberration was associated with cancer progression such that the larger the aberration, the shorter the disease-free interval (time from initial diagnosis to metastasis; r = -0.30, p = 0.004; linear regression). The same aberrant spike was present in a similar percent of women without ABC and associated with concomitant sleep disruption. A greater understanding of this sleep-related cortisol abnormality, possibly a vulnerability trait, is likely important in our understanding of individual variation in the progression of cancer.

    View details for DOI 10.1007/s10549-016-3864-2

    View details for Web of Science ID 000379494200005

    View details for PubMedID 27314577

    View details for PubMedCentralID PMC4938753

  • Temporal integration of light flashes by the human circadian system JOURNAL OF CLINICAL INVESTIGATION Najjar, R. P., Zeitzer, J. M. 2016; 126 (3): 938-947


    Beyond image formation, the light that is detected by retinal photoreceptors influences subcortical functions, including circadian timing, sleep, and arousal. The physiology of nonimage-forming (NIF) photoresponses in humans is not well understood; therefore, the development of therapeutic interventions based on this physiology, such as bright light therapy to treat chronobiological disorders, remains challenging.Thirty-nine participants were exposed to 60 minutes of either continuous light (n = 8) or sequences of 2-millisecond light flashes (n = 31) with different interstimulus intervals (ISIs; ranging from 2.5 to 240 seconds). Melatonin phase shift and suppression, along with changes in alertness and sleepiness, were assessed.We determined that the human circadian system integrates flash sequences in a nonlinear fashion with a linear rise to a peak response (ISI = 7.6 ± 0.53 seconds) and a power function decrease following the peak of responsivity. At peak ISI, flashes were at least 2-fold more effective in phase delaying the circadian system as compared with exposure to equiluminous continuous light 3,800 times the duration. Flashes did not change melatonin concentrations or alertness in an ISI-dependent manner.We have demonstrated that intermittent light is more effective than continuous light at eliciting circadian changes. These findings cast light on the phenomenology of photic integration and suggest a dichotomous retinohypothalamic network leading to circadian phase shifting and other NIF photoresponses. Further clinical trials are required to judge the practicality of light flash NCT01119365.National Heart, Lung, and Blood Institute (1R01HL108441-01A1) and Department of Veterans Affairs Sierra Pacific Mental Illness Research, Education, and Clinical Center.

    View details for DOI 10.1172/JCI82306

    View details for Web of Science ID 000371193700015

    View details for PubMedID 26854928

  • Ubiquity of Undiagnosed Sleep Disordered Breathing in Community-Dwelling Older Male Veterans. American journal of geriatric psychiatry Iqbal, N., Kinoshita, L. M., Noda, A., Friedman, L., Yesavage, J. A., Zeitzer, J. M. 2016; 24 (2): 170-173


    To determine the point prevalence of sleep disordered breathing (SDB) in a community-based sample of older male veterans and to determine if common markers of SDB apply to this population.Two hundred fourteen older male Veterans (age 55-89 years) were recruited for a study on post-traumatic stress disorder and cognitive decline. Questionnaires concerning anthropomorphic and psychological variables were obtained, as was an overnight polysomnographic examination of sleep.Only 13% of the participants lacked clinically meaningful SDB, whereas 33% had moderate SDB and 54% had severe SDB. Being overweight, self-reported snoring, and excessive daytime sleepiness all had good sensitivity (0.86-0.92) but very poor specificity (0.10-0.28) for the prediction of SDB.Undiagnosed SDB was more than threefold higher than expected in these community-dwelling older veterans. Traditional markers of SDB were not specific for predicting clinically relevant SDB.

    View details for DOI 10.1016/j.jagp.2015.08.004

    View details for PubMedID 26778348

  • Sleep Disturbance, Diabetes, and Cardiovascular Disease in Postmenopausal Veteran Women GERONTOLOGIST Rissling, M. B., Gray, K. E., Ulmer, C. S., Martin, J. L., Zaslavsky, O., Gray, S. L., Hale, L., Zeitzer, J. M., Naughton, M., Woods, N. F., LaCroix, A., Calhoun, P. S., Stefanick, M., Weitlauf, J. C. 2016; 56: S54-S66


    To compare the prevalence and cardiometabolic health impact of sleep disturbance among postmenopausal Veteran and non-Veteran participants in the Women's Health Initiative (WHI).The prevalence of five categories of sleep disturbance--medication/alcohol use for sleep; risk for insomnia; risk for sleep disordered breathing [SDB]; risk for comorbid insomnia and SDB (insomnia + SDB); and aberrant sleep duration [SLD]--was compared in 3,707 Veterans and 141,354 non-Veterans using logistic or multinomial regression. Cox proportional hazards models were used to evaluate the association of sleep disturbance and incident cardiovascular disease (CVD) and Type 2 diabetes in Veterans and non-Veterans.Women Veterans were more likely to have high risk for insomnia + SDB relative to non-Veteran participants. However, prevalence of other forms of sleep disturbance was similar across groups. Baseline sleep disturbance was not differentially associated with cardiometabolic health outcomes in Veteran versus non-Veteran women. Risks for SDB and insomnia + SDB were both linked to heightened risk of CVD and diabetes; SLD was consistently linked with greater risk of CVD and diabetes in non-Veterans but less strongly and consistently in Veterans.Efforts to identify and treat sleep disturbances in postmenopausal women are needed and may positively contribute to the attenuation of cardiometabolic morbidity risk. Increased awareness of women Veterans' vulnerability to postmenopausal insomnia + SDB may be particularly important for health care providers who treat this population.

    View details for DOI 10.1093/geront/gnv668

    View details for Web of Science ID 000374221500007

    View details for PubMedID 26768391

  • Standing Balance and Spatiotemporal Aspects of Gait Are Impaired Upon Nocturnal Awakening in Healthy Late Middle-Aged and Older Adults JOURNAL OF CLINICAL SLEEP MEDICINE McBean, A. L., Najjar, R. P., Schuchard, R. A., Hall, C. D., Wang, C., Ku, B., Zeitzer, J. M. 2016; 12 (11): 1477-1486


    Nocturnal awakenings may constitute a unique risk for falls among older adults. We describe differences in gait and balance between presleep and midsleep testing, and whether changes in the lighting environment during the midsleep testing further affect gait and balance.Twenty-one healthy, late middle-aged and older (64.7 ± 8.0 y) adults participated in this repeated-measures design consisting of four overnight laboratory stays. Each night, participants completed baseline visual acuity, gait, and balance testing. After a 2-h sleep opportunity, they were awakened for 13 min into one of four lighting conditions: very dim white light (< 0.5 lux); dim white light (∼28.0 lux); dim orange light (∼28.0 lux); and white room-level light (∼200 lux). During this awakening, participants completed the same sequence of testing as at baseline.Low-contrast visual acuity significantly decreased with decreasing illuminance conditions (F(3,45) = 98.26, p < 0.001). Our a priori hypothesis was confirmed in that variation in stride velocity and center of pressure path length were significantly worse during the mid-sleep awakening compared to presleep baseline. Lighting conditions during the awakening, however, did not influence these parameters. In exploratory analyses, we found that over one-third of the tested gait and balance parameters were significantly worse at the midsleep awakening as compared to baseline (p < 0.05), and nearly one-quarter had medium to large effect sizes (Cohen d ≥ 0.5; r ≥ 0.3).Balance and gait are impaired during midsleep awakenings among healthy, late middle-aged and older adults. This impairment is not ameliorated by exposure to room lighting, when compared to dim lights.

    View details for DOI 10.5664/jcsm.6270

    View details for Web of Science ID 000389996700007

    View details for PubMedID 27448415

  • Nocturia Reported in Nightly Sleep Diaries: Common Occurrence With Significant Implications? HEALTH PSYCHOLOGY Bliwise, D. L., Friedman, L., Hernandez, B., Zeitzer, J. M., Kushida, C. A., Yesavage, J. A. 2014; 33 (11): 1362-1365

    View details for DOI 10.1037/a0034401

    View details for Web of Science ID 000344010300011

  • Nocturia reported in nightly sleep diaries: common occurrence with significant implications? Health psychology Bliwise, D. L., Friedman, L., Hernandez, B., Zeitzer, J. M., Kushida, C. A., Yesavage, J. A. 2014; 33 (11): 1362-1365


    Nocturia (nocturnal awakenings associated with urination) is so common a nocturnal behavior that its association with poor sleep is often overlooked. This study examined nocturia and its potential role in poor sleep by examining reported nightly awakenings and associated bathroom trips.Sleep diaries were kept by 119 adults with poor sleep for intervals up to 14 days. Diaries collected data on nightly number of awakenings and nightly number of bathroom trips. The proportion of nocturnal awakenings accompanied by voiding for each night was calculated and averaged within each individual. Demographics and various health conditions were examined in relation to this measure.Nocturia was defined when at least two-thirds of all awakenings were associated with nocturnal voiding. Absence of nocturia was defined when less than one-third of awakenings were associated with voiding. Remaining cases were defined as having possible nocturia. Estimates of nocturia derived from prestudy screening were related to nocturia as defined by sleep diaries. Neither gender nor sleep apnea was associated with nocturia. Unadjusted analyses indicated that individuals with nocturia were more likely to have arthritis and attribute their nighttime awakenings to urge to void than individuals without nocturia.Nocturia is an exceedingly common phenomenon and may be associated with multiple morbidities. RESULTS are discussed in terms of causality and whether the perceived urge to void precedes or follows nocturnal awakening. Correlates of nocturia have important implications, because they can inform interventions that target brain (e.g., cognitive-behavioral treatments for insomnia, sedative/hypnotic medications) versus bladder (e.g., bladder control exercises, medications affecting urine production or urgency).

    View details for DOI 10.1037/a0034401

    View details for PubMedID 24245840

  • Millisecond flashes of light phase delay the human circadian clock during sleep. Journal of biological rhythms Zeitzer, J. M., Fisicaro, R. A., Ruby, N. F., Heller, H. C. 2014; 29 (5): 370-376


    The human circadian timing system is most sensitive to the phase-shifting effects of light during the biological nighttime, a time at which humans are most typically asleep. The overlap of sleep with peak sensitivity to the phase-shifting effects of light minimizes the effectiveness of using light as a countermeasure to circadian misalignment in humans. Most current light exposure treatments for such misalignment are mostly ineffective due to poor compliance and secondary changes that cause sleep deprivation. Using a 16-day, parallel group design, we examined whether a novel sequence of light flashes delivered during sleep could evoke phase changes in the circadian system without disrupting sleep. Healthy volunteers participated in a 2-week circadian stabilization protocol followed by a 2-night laboratory stay. During the laboratory session, they were exposed during sleep to either darkness (n = 7) or a sequence of 2-msec light flashes given every 30 sec (n = 6) from hours 2 to 3 after habitual bedtime. Changes in circadian timing (phase) and micro- and macroarchitecture of sleep were assessed. Subjects exposed to the flash sequence during sleep exhibited a delay in the timing of their circadian salivary melatonin rhythm compared with the control dark condition (p < 0.05). Confirmation that the flashes penetrated the eyelids is presented by the occurrence of an evoked response in the EEG. Despite the robust effect on circadian timing, there were no large changes in either the amount or spectral content of sleep (p values > 0.30) during the flash stimulus. Exposing sleeping individuals to 0.24 sec of light spread over an hour shifted the timing of the circadian clock and did so without major alterations to sleep itself. While a greater number of matched subjects and more research will be necessary to ascertain whether these light flashes affect sleep, our data suggest that this type of passive phototherapy might be developed as a useful treatment for circadian misalignment in humans.

    View details for DOI 10.1177/0748730414546532

    View details for PubMedID 25227334

  • Millisecond Flashes of Light Phase Delay the Human Circadian Clock during Sleep JOURNAL OF BIOLOGICAL RHYTHMS Zeitzer, J. M., Fisicaro, R. A., Ruby, N. F., Heller, H. C. 2014; 29 (5): 370-376
  • Bedtime misalignment and progression of breast cancer. Chronobiology international Hahm, B., Jo, B., Dhabhar, F. S., Palesh, O., Aldridge-Gerry, A., Bajestan, S. N., Neri, E., Nouriani, B., Spiegel, D., Zeitzer, J. M. 2014; 31 (2): 214-221


    Disruption of circadian rhythms, which frequently occurs during night shift work, may be associated with cancer progression. The effect of chronotype (preference for behaviors such as sleep, work, or exercise to occur at particular times of day, with an associated difference in circadian physiology) and alignment of bedtime (preferred vs. habitual), however, have not yet been studied in the context of cancer progression in women with breast cancer. Chronotype and alignment of actual bedtime with preferred chronotype were examined using the Morningness-Eveningness Scale (MEQ) and sleep-wake log among 85 women with metastatic breast cancer. Their association with disease-free interval (DFI) was retrospectively examined using the Cox proportional hazards model. Median DFI was 81.9 months for women with aligned bedtimes ("going to bed at preferred bedtime") (n = 72), and 46.9 months for women with misaligned bedtimes ("going to bed later or earlier than the preferred bedtime") (n = 13) (log rank p = 0.001). In a multivariate Cox proportional hazard model, after controlling for other significant predictors of DFI, including chronotype (morning type/longer DFI; HR = 0.539, 95% CI = 0.320-0.906, p = 0.021), estrogen receptor (ER) status at initial diagnosis (negative/shorter DFI; HR = 2.169, 95% CI = 1.124-4.187, p = 0.028) and level of natural-killer cell count (lower levels/shorter DFI; HR = 1.641, 95% CI = 1.000-2.695, p = 0.050), misaligned bedtimes was associated with shorter DFI, compared to aligned bedtimes (HR = 3.180, 95% CI = 1.327-7.616, p = 0.018). Our data indicate that a misalignment of bedtime on a daily basis, an indication of circadian disruption, is associated with more rapid breast cancer progression as measured by DFI. Considering the limitations of small sample size and study design, a prospective study with a larger sample is necessary to explore their causal relationship and underlying mechanisms.

    View details for DOI 10.3109/07420528.2013.842575

    View details for PubMedID 24156520

  • Effects of body mass index-related disorders on cognition: preliminary results. Diabetes, metabolic syndrome and obesity : targets and therapy Yesavage, J. A., Kinoshita, L. M., Noda, A., Lazzeroni, L. C., Fairchild, J. K., Taylor, J., Kulick, D., Friedman, L., Cheng, J., Zeitzer, J. M., O'Hara, R. 2014; 7: 145-151


    Well-known risk factors for cognitive impairment are also associated with obesity. Research has highlighted genetic risk factors for obesity, yet the relationship of those risk factors with cognitive impairment is unknown. The objective of this study was to determine the associations between cognition, hypertension, diabetes, sleep-disordered breathing, and obesity. Genetic risk factors of obesity were also examined.The sample consisted of 369 nondemented individuals aged 50 years or older from four community cohorts. Primary outcome measures included auditory verbal memory, as measured by the Rey Auditory Verbal Learning Test, and executive functioning, as measured by the Color-Word Interference Test of the Delis-Kaplan Executive Function System battery. Apnea-hypopnea index indicators were determined during standard overnight polysomnography. Statistical analyses included Pearson correlations and linear regressions.Poor executive function and auditory verbal memory were linked to cardiovascular risk factors, but not directly to obesity. Genetic factors appeared to have a small but measureable association to obesity.A direct linkage between obesity and poor executive function and auditory verbal memory is difficult to discern, possibly because nonobese individuals may show cognitive impairment due to insulin resistance and the "metabolic syndrome".

    View details for DOI 10.2147/DMSO.S60294

    View details for PubMedID 24855383

  • Randomized controlled trial of pharmacological replacement of melatonin for sleep disruption in individuals with tetraplegia JOURNAL OF SPINAL CORD MEDICINE Zeitzer, J. M., Ku, B., Ota, D., Kiratli, B. J. 2014; 37 (1): 46-53


    To determine the effectiveness of a melatonin agonist for treating sleep disturbances in individuals with tetraplegia.Placebo-controlled, double-blind, crossover, randomized control trial.At home.Eight individuals with tetraplegia, having an absence of endogenous melatonin production and the presence of a sleep disorder. Interventions Three weeks of 8 mg of ramelteon (melatonin agonist) and 3 weeks of placebo (crossover, randomized order) with 2 weeks of baseline prior to and 2 weeks of washout between active conditions.Change in objective and subjective sleep.Wrist actigraphy, post-sleep questionnaire, Stanford sleepiness scale, SF-36.We observed no consistent changes in either subjective or objective measures of sleep, including subjective sleep latency (P = 0.55, Friedman test), number of awakenings (P = 0.17, Friedman test), subjective total sleep time (P = 0.45, Friedman test), subjective morning alertness (P = 0.35, Friedman test), objective wake after sleep onset (P = 0.70, Friedman test), or objective sleep efficiency (P = 0.78, Friedman test). There were significant increases in both objective total sleep time (P < 0.05, Friedman test), subjective time in bed (P < 0.05, Friedman test), and subjective sleep quality (P < 0.05, Friedman test), although these occurred in both arms. There were no significant changes in any of the nine SF-36 subscale scores (Friedman test, Ps >Bonferroni adjusted α of 0.005).In this pilot study, we were unable to show effectiveness of pharmacological replacement of melatonin for the treatment of self-reported sleep problems in individuals with tetraplegia. Trial Registration # NCT00507546.

    View details for DOI 10.1179/2045772313Y.0000000099

    View details for Web of Science ID 000337132500007

    View details for PubMedID 24090266

  • Correspondence of plasma and salivary cortisol patterns in women with breast cancer. Neuroendocrinology Zeitzer, J. M., Nouriani, B., Neri, E., Spiegel, D. 2014; 100 (2-3): 153-161


    The 'diurnal slope' of salivary cortisol has been used as a measure of stress and circadian function in a variety of reports with several detailing its association with cancer progression. The relationship of this slope, typically a negative value from high morning concentrations to low evening concentrations, to the underlying daily variation in total plasma cortisol throughout the 24-hour cycle, however, has never been reported.To examine the relationship between the diurnal salivary cortisol slope and the underlying pattern of plasma cortisol in individuals with cancer, we examined a cohort of women with advanced breast cancer (n = 97) who had saliva and plasma collected during a modified 24-hour, constant posture protocol.We found that the steepness of the diurnal slope of salivary cortisol was correlated with the amplitude of plasma cortisol rhythm when the slope was calculated from samples taken at wake + 30 min and 9 PM (r = -0.29, p > 0.05). Other variants of salivary slope calculations were not significantly correlated with the amplitude of the plasma cortisol rhythm. Diurnal salivary cortisol slope steepness was not correlated with the time between habitual waking and the computed circadian peak of cortisol, but there was a correlation between diurnal slope steepness and the time between habitual waking and the time of the awakening spike of morning cortisol (r values <-0.23, p values <0.05).It therefore appears that in women with advanced breast cancer, diurnal salivary cortisol slope primarily represents aspects of the cortisol awakening response in relation to evening levels more than the circadian rhythm of total plasma cortisol. © 2014 S. Karger AG, Basel.

    View details for DOI 10.1159/000367925

    View details for PubMedID 25228297

  • Longitudinal assessment of sleep disordered breathing in Vietnam veterans with post-traumatic stress disorder. Nature and science of sleep Yesavage, J. A., Kinoshita, L. M., Noda, A., Lazzeroni, L. C., Fairchild, J. K., Friedman, L., Sekhon, G., Thompson, S., Cheng, J., Zeitzer, J. M. 2014; 6: 123-127


    Previous work has demonstrated the relatively high prevalence of risk factors for cognitive impairment, such as sleep disordered breathing (SDB) and obesity, in Vietnam War era veterans with post-traumatic stress disorder (PTSD). No data are currently available on the longitudinal stability of SDB as a risk factor for cognitive decline in that population, which this study now reports.Sample consisted of 48 veterans of the Vietnam War with PTSD who completed longitudinal sleep assessments over a 3-year period. The primary outcome measure, the Apnea-Hypopnea Index (AHI) indicator, was determined during standard overnight polysomnography. Body mass index (BMI) was calculated using standard measurements. Measures of cognitive function tapped auditory verbal memory as measured by the Rey Auditory Verbal Learning Test and executive functioning as measured by the Color-Word Interference Test of the Delis-Kaplan Executive Function System battery. Statistical analyses included mixed effects modeling.In this sample, AHI increased significantly by 2.19 points per year (β=2.19; P<0.005). AHI worsened over the 3-year period, increasing from a mean of 18.7±15.7 to 24.7±17.4 points. Neither BMI nor cognition showed significant change over the 3-year period.SDB worsened in a group of veterans of the Vietnam War with PTSD over a 3-year period. The worsening of SDB over time suggests the need for appropriate countermeasures in populations at risk for progression of the condition.

    View details for DOI 10.2147/NSS.S65034

    View details for PubMedID 25378962

    View details for PubMedCentralID PMC4219637

  • Retino-hypothalamic regulation of light-induced murine sleep. Frontiers in systems neuroscience Muindi, F., Zeitzer, J. M., Heller, H. C. 2014; 8: 135-?


    The temporal organization of sleep is regulated by an interaction between the circadian clock and homeostatic processes. Light indirectly modulates sleep through its ability to phase shift and entrain the circadian clock. Light can also exert a direct, circadian-independent effect on sleep. For example, acute exposure to light promotes sleep in nocturnal animals and wake in diurnal animals. The mechanisms whereby light directly influences sleep and arousal are not well understood. In this review, we discuss the direct effect of light on sleep at the level of the retina and hypothalamus in rodents. We review murine data from recent publications showing the roles of rod-, cone- and melanopsin-based photoreception on the initiation and maintenance of light-induced sleep. We also present hypotheses about hypothalamic mechanisms that have been advanced to explain the acute control of sleep by light. Specifically, we review recent studies assessing the roles of the ventrolateral preoptic area (VLPO) and the suprachiasmatic nucleus (SCN). We also discuss how light might differentially promote sleep and arousal in nocturnal and diurnal animals respectively. Lastly, we suggest new avenues for research on this topic which is still in its early stages.

    View details for DOI 10.3389/fnsys.2014.00135

    View details for PubMedID 25140132

  • Actigraphy-Measured Sleep Disruption as a Predictor of Survival among Women with Advanced Breast Cancer. Sleep Palesh, O., Aldridge-Gerry, A., Zeitzer, J. M., Koopman, C., Neri, E., Giese-Davis, J., Jo, B., Kraemer, H., Nouriani, B., Spiegel, D. 2014; 37 (5): 837-842


    Poor sleep, prevalent among cancer survivors, is associated with disrupted hormonal circadian rhythms and poor quality of life. Using a prospective research design, this study aimed to clarify the relationship between objective measures of sleep efficiency and sleep disruption with survival among women with advanced breast cancer.We examined sleep quality and duration via wrist-worn actigraphy and sleep diaries for 3 days among 97 women in whom advanced breast cancer was diagnosed (age = 54.6 ± 9.8 years). Sleep efficiency was operationalized using actigraphy as the ratio of total sleep time to total sleep time plus wake after sleep onset.As hypothesized, better sleep efficiency was found to predict a significant reduction in overall mortality (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.94-0.98; P < 0.001) at median 6 y follow-up. This relationship remained significant (HR, 0.94; 95% CI, 0.91-0.97; P < 0.001) even after adjusting for other known prognostic factors (age, estrogen receptor status, cancer treatment, metastatic spread, cortisol levels, and depression). Secondary hypotheses were also supported (after adjusting for baseline prognostic factors) showing that less wake after sleep onset (HR, 0.41; 95% CI, 0.25-0.67; P < 0.001), fewer wake episodes, (HR, 0.93; 95% CI, 0.88-0.98; P = 0.007); and shorter wake episode duration (HR, 0.29; 95% CI, 0.14-0.58; P < 0.001) also contributed to reductions in overall mortality.These findings show that better sleep efficiency and less sleep disruption are significant independent prognostic factors in women with advanced breast cancer. Further research is needed to determine whether treating sleep disruption with cognitive behavioral and/or pharmacologic therapy could improve survival in women with advanced breast cancer.

    View details for DOI 10.5665/sleep.3642

    View details for PubMedID 24790261

  • Psychosocial correlates of sleep quality and architecture in women with metastatic breast cancer. Sleep medicine Aldridge-Gerry, A., Zeitzer, J. M., Palesh, O. G., Jo, B., Nouriani, B., Neri, E., Spiegel, D. 2013; 14 (11): 1178-1186


    Sleep disturbance is prevalent among women with metastatic breast cancer (MBC). Our study examined the relationship of depression and marital status to sleep assessed over three nights of polysomnography (PSG).Women with MBC (N=103) were recruited; they were predominately white (88.2%) and 57.8±7.7 years of age. Linear regression analyses assessed relationships among depression, marital status, and sleep parameters.Women with MBC who reported more depressive symptoms had lighter sleep (e.g., stage 1 sleep; P<.05), less slow-wave sleep (SWS) (P<.05), and less rapid eye movement (REM) sleep (P<.05). Single women had less total sleep time (TST) (P<.01), more wake after sleep onset (WASO) (P<.05), worse sleep efficiency (SE) (P<.05), lighter sleep (e.g., stage 1; P<.05), and less REM sleep (P<.05) than married women. Significant interactions indicated that depressed and single women had worse sleep quality than partnered women or those who were not depressed.Women with MBC and greater symptoms of depression had increased light sleep and reduced SWS and REM sleep, and single women had worse sleep quality and greater light sleep than married counterparts. Marriage was related to improved sleep for women with more depressive symptoms.

    View details for DOI 10.1016/j.sleep.2013.07.012

    View details for PubMedID 24074694

  • Psychosocial correlates of sleep quality and architecture in women with metastatic breast cancer SLEEP MEDICINE Aldridge-Gerry, A., Zeitzer, J. M., Palesh, O. G., Jo, B., Nouriani, B., Neri, E., Spiegel, D. 2013; 14 (11): 1178-1186


    Sleep disturbance is prevalent among women with metastatic breast cancer (MBC). Our study examined the relationship of depression and marital status to sleep assessed over three nights of polysomnography (PSG).Women with MBC (N=103) were recruited; they were predominately white (88.2%) and 57.8±7.7 years of age. Linear regression analyses assessed relationships among depression, marital status, and sleep parameters.Women with MBC who reported more depressive symptoms had lighter sleep (e.g., stage 1 sleep; P<.05), less slow-wave sleep (SWS) (P<.05), and less rapid eye movement (REM) sleep (P<.05). Single women had less total sleep time (TST) (P<.01), more wake after sleep onset (WASO) (P<.05), worse sleep efficiency (SE) (P<.05), lighter sleep (e.g., stage 1; P<.05), and less REM sleep (P<.05) than married women. Significant interactions indicated that depressed and single women had worse sleep quality than partnered women or those who were not depressed.Women with MBC and greater symptoms of depression had increased light sleep and reduced SWS and REM sleep, and single women had worse sleep quality and greater light sleep than married counterparts. Marriage was related to improved sleep for women with more depressive symptoms.

    View details for DOI 10.1016/j.sleep.2013.07.012

    View details for Web of Science ID 000326625400021

    View details for PubMedID 24074694

  • A survey study of the association between mobile phone use and daytime sleepiness in California high school students BMC PUBLIC HEALTH Nathan, N., Zeitzer, J. 2013; 13


    Mobile phone use is near ubiquitous in teenagers. Paralleling the rise in mobile phone use is an equally rapid decline in the amount of time teenagers are spending asleep at night. Prior research indicates that there might be a relationship between daytime sleepiness and nocturnal mobile phone use in teenagers in a variety of countries. As such, the aim of this study was to see if there was an association between mobile phone use, especially at night, and sleepiness in a group of U.S. teenagers.A questionnaire containing an Epworth Sleepiness Scale (ESS) modified for use in teens and questions about qualitative and quantitative use of the mobile phone was completed by students attending Mountain View High School in Mountain View, California (n = 211).Multivariate regression analysis indicated that ESS score was significantly associated with being female, feeling a need to be accessible by mobile phone all of the time, and a past attempt to reduce mobile phone use. The number of daily texts or phone calls was not directly associated with ESS. Those individuals who felt they needed to be accessible and those who had attempted to reduce mobile phone use were also ones who stayed up later to use the mobile phone and were awakened more often at night by the mobile phone.The relationship between daytime sleepiness and mobile phone use was not directly related to the volume of texting but may be related to the temporal pattern of mobile phone use.

    View details for DOI 10.1186/1471-2458-13-840

    View details for Web of Science ID 000324370300001

    View details for PubMedID 24028604

  • The acute effects of light on murine sleep during the dark phase: importance of melanopsin for maintenance of light-induced sleep. European journal of neuroscience Muindi, F., Zeitzer, J. M., Colas, D., Heller, H. C. 2013; 37 (11): 1727-1736


    Light exerts a direct effect on sleep and wakefulness in nocturnal and diurnal animals, with a light pulse during the dark phase suppressing locomotor activity and promoting sleep in the former. In the present study, we investigated this direct effect of light on various sleep parameters by exposing mice to a broad range of illuminances (0.2-200 μW/cm(2) ; equivalent to 1-1000 lux) for 1 h during the dark phase (zeitgeber time 13-14). Fitting the data with a three-parameter log model indicated that ∼0.1 μW/cm(2) can generate half the sleep response observed at 200 μW/cm(2) . We observed decreases in total sleep time during the 1 h following the end of the light pulse. Light reduced the latency to sleep from ~30 min in darkness (baseline) to ~10 min at the highest intensity, although this effect was invariant across the light intensities used. We then assessed the role of melanopsin during the rapid transition from wakefulness to sleep at the onset of a light pulse and the maintenance of sleep with a 6-h 20 μW/cm(2) light pulse. Even though the melanopsin knockout mice had robust induction of sleep (~35 min) during the first hour of the pulse, it was not maintained. Total sleep decreased by almost 65% by the third hour in comparison with the first hour of the pulse in mice lacking melanopsin, whereas only an 8% decrease was observed in wild-type mice. Collectively, our findings highlight the selective effects of light on murine sleep, and suggest that melanopsin-based photoreception is primarily involved in sustaining light-induced sleep.

    View details for DOI 10.1111/ejn.12189

    View details for PubMedID 23510299

  • Phenotyping apathy in individuals with Alzheimer disease using functional principal component analysis. American journal of geriatric psychiatry Zeitzer, J. M., David, R., Friedman, L., Mulin, E., Garcia, R., Wang, J., Yesavage, J. A., Robert, P. H., Shannon, W. 2013; 21 (4): 391-397


    To determine if there is a specific pattern of gross motor activity associated with apathy in individuals with Alzheimer disease (AD).Examination of ad libitum 24-hour ambulatory gross motor activity patterns.Community-dwelling, outpatient.Ninety-two individuals with AD, 35 of whom had apathy.Wrist actigraphy data were collected and examined using functional principal component analysis (fPCA).Individuals with apathy have a different pattern of gross motor activity than those without apathy (first fPCA component, p <0.0001, t = 5.73, df = 90, t test) such that there is a pronounced decline in early afternoon activity in those with apathy. This change in activity is independent of depression (p = 0.68, F[1, 89] = 0.05, analysis of variance). The decline in activity is consistent with an increase in napping. Those with apathy also have an early wake and bedtime (second fPCA component, t = 2.53, df = 90, p <0.05, t test).There is a signature activity pattern in individuals with apathy and AD that is distinct from those without apathy and those with depression. Actigraphy may be a useful adjunctive measurement in the clinical diagnosis of apathy in the context of AD.

    View details for DOI 10.1016/j.jagp.2012.12.012

    View details for PubMedID 23498386

  • Nocturia Compounds Nocturnal Wakefulness in Older Individuals with Insomnia JOURNAL OF CLINICAL SLEEP MEDICINE Zeitzer, J. M., Bliwise, D. L., Hernandez, B., Friedman, L., Yesavage, J. A. 2013; 9 (3): 259-262


    To determine the impact of nocturia on objective measures of sleep in older individuals with insomnia.The sleep and toileting patterns of a group of community-dwelling older men (n = 55, aged 64.3 ± 7.52 years) and women (n = 92, aged 62.5 ± 6.73 years) with insomnia were studied for two weeks using sleep logs and one week using actigraphy. The relationships between nocturia and various sleep parameters were analyzed with ANOVA and linear regression.More than half (54.2% ± 39.9%) of all log-reported nocturnal awakenings were associated with nocturia. A greater number of trips to the toilet was associated with worse log-reported restedness (p < 0.01) and sleep efficiency (p < 0.001), as well as increases in actigraph-derived measures of the number and length of nocturnal wake bouts (p < 0.001) and wake after sleep onset (p < 0.001). Actigraph-determined wake bouts were 11.5% ± 23.5% longer on nights on which there was a trip to the toilet and wake after sleep onset was 20.8% ± 33.0% longer during these nights.Nocturia is a common occurrence in older individuals with insomnia and is significantly associated with increased nocturnal wakefulness and decreased subjective restedness after sleep.

    View details for DOI 10.5664/jcsm.2492

    View details for Web of Science ID 000316209800010

    View details for PubMedID 23493881

  • Modeling the effects of obstructive sleep apnea and hypertension in Vietnam veterans with PTSD SLEEP AND BREATHING Kinoshita, L. M., Yesavage, J. A., Noda, A., Jo, B., Hernandez, B., Taylor, J., Zeitzer, J. M., Friedman, L., Fairchild, J. K., Cheng, J., Kuschner, W., O'Hara, R., Holty, J. C., Scanlon, B. K. 2012; 16 (4): 1201-1209


    The present work aimed to extend models suggesting that obstructive sleep apnea (OSA) is associated with worse cognitive performance in community-dwelling older adults. We hypothesized that in addition to indices of OSA severity, hypertension is associated with worse cognitive performance in such adults.The PTSD Apnea Clinical Study recruited 120 community-dwelling, male veterans diagnosed with PTSD, ages 55 and older. The Rey Auditory Verbal Learning Test (RAVLT) and Color-Word Interference Test (CWIT) were measures of auditory verbal memory and executive function, respectively. Apnea-hypopnea index (AHI), minimum and mean pulse oximeter oxygen saturation (min SpO(2), mean SpO(2)) indicators were determined during standard overnight polysomnography. Multivariate linear regression and receiver operating characteristic (ROC) curve analyses were performed.In regression models, AHI (β = -4.099; p < 0.01) and hypertension (β = -4.500; p < 0.05) predicted RAVLT; hypertension alone (β = 9.146; p < 0.01) predicted CWIT. ROC analyses selected min SpO(2) cut-points of 85% for RAVLT (κ = 0.27; χ² = 8.23, p < 0.01) and 80% for CWIT (κ = 0.25; χ² = 12.65, p < 0.01). Min SpO(2) cut-points and hypertension were significant when added simultaneously in a regression model for RAVLT (min SpO(2), β = 4.452; p < 0.05; hypertension, β = -4.332; p < 0.05), and in separate models for CWIT (min SpO(2), β = -8.286; p < 0.05; hypertension, β = -8.993; p < 0.01).OSA severity and presence of self-reported hypertension are associated with poor auditory verbal memory and executive function in older adults.

    View details for DOI 10.1007/s11325-011-0632-8

    View details for Web of Science ID 000311301700038

    View details for PubMedID 22193972

  • Decreased Daytime Motor Activity Associated With Apathy in Alzheimer Disease: An Actigraphic Study AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY David, R., Mulin, E., Friedman, L., Le Duff, F., Cygankiewicz, E., Deschaux, O., Garcia, R., Yesavage, J. A., Robert, P. H., Zeitzer, J. M. 2012; 20 (9): 806-814


    Across all stages of Alzheimer disease (AD), apathy is the most common neuropsychiatric symptom. Studies using the Neuropsychiatric Inventory (NPI) have found that apathy is present in up to 70% of individuals with Alzheimer disease. One of the main difficulties in assessing apathy and other neuropsychiatric symptoms is the absence of reliable, objective measures. Motor activity assessment using ambulatory actigraphy could provide an indirect, objective evaluation of apathy. The aim of our study was to assess the relationship between apathy and daytime motor activity in AD, using ambulatory actigraphy.One hundred seven AD outpatients wore a wrist actigraph (Motionlogger) during seven consecutive 24-hour periods to evaluate motor activity. Participants were divided into two subgroups according to their apathy subscores on the NPI: individuals with apathy (NPI-apathy subscores >4) and those without. Daytime mean motor activity scores were compared between the two subgroups.Individuals with AD who had symptoms of apathy (n = 43; age = 79 ± 4.7 years; Mini-Mental State Examination = 20.9 ± 4.8) had significantly lower daytime mean motor activity than AD patients without apathy (n = 64; age = 76.3 ± 7.7; Mini-Mental State Examination = 21.5 ± 4.7), while nighttime mean motor activity did not significantly differ between the two subgroups.Ambulatory actigraphy could be added to currently used questionnaires as a simple, objective technique for assessing apathy in the routine assessment of AD patients.

    View details for DOI 10.1097/JGP.0b013e31823038af

    View details for Web of Science ID 000308078500010

    View details for PubMedID 21997602

  • Psychosocial correlates of sleep architecture in women with advanced breast cancer. 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Gerry, A. A., Jo, B., Palesh, O., Zeitzer, J., Neri, E., Spiegel, D. AMER SOC CLINICAL ONCOLOGY. 2012
  • Brief morning light treatment for sleep/wake disturbances in older memory-impaired individuals and their caregivers SLEEP MEDICINE Friedman, L., Spira, A. P., Hernandez, B., Mather, C., Sheikh, J., Ancoli-Israel, S., Yesavage, J. A., Zeitzer, J. M. 2012; 13 (5): 546-549


    Scheduled exposure to bright light (phototherapy) has been used, with varying degrees of success, to treat sleep disruption in older individuals. Most of these studies have been done in institutional settings and have used several hours of daily light exposure. Such a regimen in the home setting may be untenable, especially when the individual with the sleep disruption has memory impairment and is being cared for by a family member. As such, we examined the effectiveness of a "user-friendly" phototherapy protocol that would be readily usable in the home environment.We exposed a group of 54 older caregiver/care recipient dyads, in which the care recipient had memory impairment, to two weeks of morning bright light phototherapy. Dyads were exposed to either bright white (∼4200 lux) or dim red (∼90 lux) light for 30 min every day, starting within 30 min of rising. All subjects also received sleep hygiene therapy. Objective (actigraphy) and subjective measures of sleep and mood were obtained at baseline and at the end of the two weeks of phototherapy.In care recipients, actigraphy- and log-determined time in bed and total sleep time declined in the active condition (p<0.05, ANOVA); there was no corresponding change in subjective insomnia symptoms (p's>0.37, ANOVA). The decrease in the time in bed was associated with an earlier out of bed time in the morning (p<0.001, Pearson correlation). The decrease in the total sleep time was associated with a decrease in sleep efficiency (p<0.001, Pearson correlation) and an increase in wake after sleep onset (p<0.001, Pearson correlation). In caregivers, there were no differential changes in actigraphic measures of sleep (p's>0.05, ANOVA). Actigraphy-measured wake after sleep onset and sleep efficiency did, however, improve in both conditions, as did sleepiness, insomnia symptoms, and depressive symptomatology (p's<0.05, ANOVA).Exposure to this regimen of phototherapy diminished sleep in older individuals with memory impairments. Their caregivers, however, experienced an improvement in sleep and mood that appeared independent of the phototherapy and likely due to participation in this protocol or the sleep hygiene therapy.

    View details for DOI 10.1016/j.sleep.2011.11.013

    View details for Web of Science ID 000303346800016

    View details for PubMedID 22406033

  • Time-course of cerebrospinal fluid histamine in the wake-consolidated squirrel monkey JOURNAL OF SLEEP RESEARCH Zeitzer, J. M., Kodama, T., Buckmaster, C. L., Honda, Y., Lyons, D. M., Nishino, S., Mignot, E. 2012; 21 (2): 189-194


    Central nervous system (CNS) histamine is low in individuals with narcolepsy, a disease characterized by severe fragmentation of both sleep and wake. We have developed a primate model, the squirrel monkey, with which we can examine the role of the CNS in the wake-consolidation process, as these primates are day-active, have consolidated wake and sleep and have cerebrospinal fluid (CSF) that is readily accessible. Using this model and three distinct protocols, we report herein on the role of CNS histamine in the wake consolidation process. CSF histamine has a robust daily rhythm, with a mean of 24.9 ± 3.29 pg mL(-1) , amplitude of 31.7 ± 6.46 pg mL(-1) and a peak at 17:49 ± 70.3 min (lights on 07:00-19:00 hours). These levels are not significantly affected by increases (up to 161 ± 40.4% of baseline) or decreases (up to 17.2 ± 2.50% of baseline) in locomotion. In direct contrast to the effects of sleep deprivation in non-wake-consolidating mammals, in whom CSF histamine increases, pharmacologically induced sleep (γ-hydroxybutyrate) and wake (modafinil) have no direct effects on CSF histamine concentrations. These data indicate that the time-course of histamine in CSF in the wake-consolidated squirrel monkey is robust against variation in activity and sleep and wake-promoting pharmacological compounds, and may indicate that histamine physiology plays a role in wake-consolidation such as is present in the squirrel monkey and humans.

    View details for DOI 10.1111/j.1365-2869.2011.00957.x

    View details for Web of Science ID 000301931500010

    View details for PubMedID 21910776

  • Modeling caffeine concentrations with the Stanford Caffeine Questionnaire: Preliminary evidence for an interaction of chronotype with the effects of caffeine on sleep SLEEP MEDICINE Nova, P., Hernandez, B., Ptolemy, A. S., Zeitzer, J. M. 2012; 13 (4): 362-367


    To examine the validity of a novel caffeine intake questionnaire and to examine the effects of caffeine on sleep in college students.One-week, ad libitum behavior of 50 university students (28 female, 22 male; aged 20.9 ± 1.78 years) was examined with sleep logs, wrist actigraphy, and a novel daily questionnaire assessing caffeine intake at different times of day. Saliva samples were collected for caffeine assessment (questionnaire validation) and DNA extraction, and for analysis of a single nucleotide polymorphism in the adenosine receptor 2A (ADORA2A) gene.The caffeine questionnaire was able to accurately predict salivary concentrations of caffeine (R(2) = 0.41, P<0.001). Estimations of integrated salivary caffeine concentration during sleep were correlated with wake after sleep onset (WASO) most strongly in morning-type individuals (R(2) = 0.49; P<0.001, ANOVA), less so in intermediate chronotypes (R(2) = 0.16; P<0.001, ANOVA), and not significantly in evening-types (R(2) = 0.00098; P = 0.13, ANOVA). Using multivariate modeling methods we found that the ADORA2A genotype did not moderate the effects of caffeine on WASO, but did independently alter WASO such that those with the CC genotype had nearly three-times as much WASO as those with CT or TT.Our questionnaire was able to accurately predict salivary caffeine concentrations and helped to describe a novel relationship between the effects of caffeine on sleep and genotype and chronotype.

    View details for DOI 10.1016/j.sleep.2011.11.011

    View details for Web of Science ID 000303346300007

    View details for PubMedID 22333316

  • Sleep-Disordered Breathing in Vietnam Veterans with Posttraumatic Stress Disorder AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Yesavage, J. A., Kinoshita, L. M., Kimball, T., Zeitzer, J., Friedman, L., Noda, A., David, R., Hernandez, B., Lee, T., Cheng, J., O'Hara, R. 2012; 20 (3): 199-204


    : To study the prevalence of sleep-disordered breathing (SDB) in Vietnam- era veterans.: This was an observational study of Vietnam-era veterans using unattended, overnight polysomnography, cognitive testing, and genetic measures.: A sample of 105 Vietnam-era veterans with posttraumatic stress disorder: 69% had an Apnea Hypopnea Index >10. Their mean body mass index was 31, "obese" by Centers for Disease Control and Prevention criteria, and body mass index was significantly associated with Apnea Hypopnea Index (Spearman r = 0.41, N = 97, p < 0.0001). No significant effects of sleep-disordered breathing or apolipoprotein status were found on an extensive battery of cognitive tests.: There is a relatively high prevalence of SDB in these patients which raises the question of to what degree excess cognitive loss in older PTSD patients may be due to a high prevalence of SDB.

    View details for DOI 10.1097/JGP.0b013e3181e446ea

    View details for Web of Science ID 000300642300002

    View details for PubMedID 20808112

  • Phenotyping Apathy in Individuals With Alzheimer Disease Using Functional Principal Component Analysis. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry Zeitzer, J. M., David, R., Friedman, L., Mulin, E., Garcia, R., Wang, J., Yesavage, J. A., Robert, P. H., Shannon, W. 2012


    OBJECTIVES:: To determine if there is a specific pattern of gross motor activity associated with apathy in individuals with Alzheimer disease (AD). DESIGN:: Examination of ad libitum 24-hour ambulatory gross motor activity patterns. SETTING:: Community-dwelling, outpatient. PARTICIPANTS:: Ninety-two individuals with AD, 35 of whom had apathy. MEASUREMENTS:: Wrist actigraphy data were collected and examined using functional principal component analysis (fPCA). RESULTS:: Individuals with apathy have a different pattern of gross motor activity than those without apathy (first fPCA component, p <0.0001, t = 5.73, df = 90, t test) such that there is a pronounced decline in early afternoon activity in those with apathy. This change in activity is independent of depression (p = 0.68, F[1, 89] = 0.05, analysis of variance). The decline in activity is consistent with an increase in napping. Those with apathy also have an early wake and bedtime (second fPCA component, t = 2.53, df = 90, p <0.05, t test). CONCLUSIONS:: There is a signature activity pattern in individuals with apathy and AD that is distinct from those without apathy and those with depression. Actigraphy may be a useful adjunctive measurement in the clinical diagnosis of apathy in the context of AD.

    View details for DOI 10.1097/JGP.0b013e318248779d

    View details for PubMedID 22367164

    View details for PubMedCentralID PMC3368995

  • Effectiveness of evening phototherapy for insomnia is reduced by bright daytime light exposure SLEEP MEDICINE Zeitzer, J. M., Friedman, L., Yesavage, J. A. 2011; 12 (8): 805-807


    To examine the effect of ambulatory daytime light exposure on phase delays and on the advances produced by timed exposure to bright evening or morning light.As a subset of a larger study, 32 older (63.0 ± 6.43 years) adults with primary insomnia were randomized to an at-home, single-blind, 12-week, parallel-group study entailing daily exposure to 45 min of scheduled evening or morning bright (∼4000 lux) light. Light exposure patterns during the baseline and the last week of treatment were monitored using actigraphs with built-in illuminance detectors. Circadian phase was determined through analysis of in-laboratory collected plasma melatonin.Less daytime light exposure during the last week of treatment was significantly associated with larger phase delays in response to evening light (r's>0.78). Less daytime light exposure during the last week of treatment was also associated with a significant delay in wake time (r's>-0.75). There were no such relationships between light exposure history and phase advances in response to morning light.Greater light exposure during the daytime may decrease the ability of evening light, but not morning light, exposure to engender meaningful changes of circadian phase.

    View details for DOI 10.1016/j.sleep.2011.02.005

    View details for Web of Science ID 000295764800013

    View details for PubMedID 21855408

  • The Roles of COMT val158met Status and Aviation Expertise in Flight Simulator Performance and Cognitive Ability BEHAVIOR GENETICS Kennedy, Q., Taylor, J. L., Noda, A., Adamson, M., Murphy, G. M., Zeitzer, J. M., Yesavage, J. A. 2011; 41 (5): 700-708


    The polymorphic variation in the val158met position of the catechol-O-methyltransferase (COMT) gene is associated with differences in executive performance, processing speed, and attention. The purpose of this study is: (1) replicate previous COMT val158met findings on cognitive performance; (2) determine whether COMT val158met effects extend to a real-world task, aircraft navigation performance in a flight simulator; and (3) determine if aviation expertise moderates any effect of COMT val158met status on flight simulator performance. One hundred seventy two pilots aged 41-69 years, who varied in level of aviation training and experience, completed flight simulator, cognitive, and genetic assessments. Results indicate that although no COMT effect was found for an overall measure of flight performance, a positive effect of the met allele was detected for two aspects of cognitive ability: executive functioning and working memory performance. Pilots with the met/met genotype benefited more from increased levels of expertise than other participants on a traffic avoidance measure, which is a component of flight simulator performance. These preliminary results indicate that COMT val158met polymorphic variation can affect a real-world task.

    View details for DOI 10.1007/s10519-010-9436-z

    View details for Web of Science ID 000294297200008

    View details for PubMedID 21193954

  • Response of the Human Circadian System to Millisecond Flashes of Light PLOS ONE Zeitzer, J. M., Ruby, N. F., Fisicaro, R. A., Heller, H. C. 2011; 6 (7)


    Ocular light sensitivity is the primary mechanism by which the central circadian clock, located in the suprachiasmatic nucleus (SCN), remains synchronized with the external geophysical day. This process is dependent on both the intensity and timing of the light exposure. Little is known about the impact of the duration of light exposure on the synchronization process in humans. In vitro and behavioral data, however, indicate the circadian clock in rodents can respond to sequences of millisecond light flashes. In a cross-over design, we tested the capacity of humans (n = 7) to respond to a sequence of 60 2-msec pulses of moderately bright light (473 lux) given over an hour during the night. Compared to a control dark exposure, after which there was a 3.5±7.3 min circadian phase delay, the millisecond light flashes delayed the circadian clock by 45±13 min (p<0.01). These light flashes also concomitantly increased subjective and objective alertness while suppressing delta and sigma activity (p<0.05) in the electroencephalogram (EEG). Our data indicate that phase shifting of the human circadian clock and immediate alerting effects can be observed in response to brief flashes of light. These data are consistent with the hypothesis that the circadian system can temporally integrate extraordinarily brief light exposures.

    View details for DOI 10.1371/journal.pone.0022078

    View details for Web of Science ID 000292657200045

    View details for PubMedID 21760955

  • Initial Cognitive Performance Predicts Longitudinal Aviator Performance JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES Yesavage, J. A., Jo, B., Adamson, M. M., Kennedy, Q., Noda, A., Hernandez, B., Zeitzer, J. M., Friedman, L. F., Fairchild, K., Scanlon, B. K., Murphy, G. M., Taylor, J. L. 2011; 66 (4): 444-453


    The goal of the study was to improve prediction of longitudinal flight simulator performance by studying cognitive factors that may moderate the influence of chronological age.We examined age-related change in aviation performance in aircraft pilots in relation to baseline cognitive ability measures and aviation expertise. Participants were aircraft pilots (N = 276) aged 40-77.9. Flight simulator performance and cognition were tested yearly; there were an average of 4.3 (± 2.7; range 1-13) data points per participant. Each participant was classified into one of the three levels of aviation expertise based on Federal Aviation Administration pilot proficiency ratings: least, moderate, or high expertise.Addition of measures of cognitive processing speed and executive function to a model of age-related change in aviation performance significantly improved the model. Processing speed and executive function performance interacted such that the slowest rate of decline in flight simulator performance was found in aviators with the highest scores on tests of these abilities. Expertise was beneficial to pilots across the age range studied; however, expertise did not show evidence of reducing the effect of age.These data suggest that longitudinal performance on an important real-world activity can be predicted by initial assessment of relevant cognitive abilities.

    View details for DOI 10.1093/geronb/gbr031

    View details for Web of Science ID 000293251900007

    View details for PubMedID 21586627

  • Circadian Clock Gene Polymorphisms and Sleep-Wake Disturbance in Alzheimer Disease AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Yesavage, J. A., Noda, A., Hernandez, B., Friedman, L., Cheng, J. J., Tinklenberg, J. R., Hallmayer, J., O'Hara, R., David, R., Robert, P., Landsverk, E., Zeitzer, J. M. 2011; 19 (7): 635-643


    One of the hypothesized causes of the breakdown in sleep-wake consolidation often occurring in individuals with Alzheimer disease (AD) is the dysfunction of the circadian clock. The goal of this study is to report indices of sleep-wake function collected from individuals with AD in relation to relevant polymorphisms in circadian clock-related genes.One week of ad libitum ambulatory sleep data collection.At-home collection of sleep data and in-laboratory questionnaire.Two cohorts of AD participants. Cohort 1 (N = 124): individuals with probable AD recruited from the Stanford/Veterans Affairs, National Institute on Aging Alzheimer's Disease Core Center (N = 81), and the Memory Disorders Clinic at the University of Nice School of Medicine (N = 43). Cohort 2 (N = 176): individuals with probable AD derived from the Alzheimer's Disease Neuroimaging Initiative data set.Determination of sleep-wake state was obtained by wrist actigraphy data for 7 days in Cohort 1 and by the Neuropsychiatric Inventory questionnaire for Cohort 2. Both cohorts were genotyped by using an Illumina Beadstation (Illumina, San Diego, CA), and 122 circadian-related single-nucleotide polymorphisms (SNPs) were examined. In Cohort 1, an additional polymorphism (variable-number tandem repeat in per3) was also determined.Adjusting for multiple tests, none of the candidate gene SNPs were significantly associated with the amount of wake time after sleep onset (WASO), a marker of sleep consolidation. Although the study was powered sufficiently to identify moderate-sized correlations, we found no relationships likely to be of clinical relevance.It is unlikely that a relationship with a clinically meaningful correlation exists between the circadian rhythm-associated SNPs and WASO in individuals with AD.

    View details for DOI 10.1097/JGP.0b013e31820d92b2

    View details for Web of Science ID 000292031900005

    View details for PubMedID 21709609

  • Faster REM sleep EEG and worse restedness in older insomniacs with HLA DQB1*0602 PSYCHIATRY RESEARCH Zeitzer, J. M., Fisicaro, R. A., Grove, M. E., Mignot, E., Yesavage, J. A., Friedman, L. 2011; 187 (3): 397-400


    HLA DQB1*0602 is found in most individuals with hypocretin-deficient narcolepsy, a disorder characterized by a severe disruption of sleep and wake. Population studies indicate that DQB1*0602 may also be associated with normal phenotypic variation of rapid eye movement (REM) sleep. Disruption of REM sleep has been linked to specific symptoms of insomnia. We here examine the relationship of sleep and DQB1*0602 in older individuals (n=46) with primary insomnia, using objective (polysomnography, wrist actigraphy) and subjective (logs, scales) measures. DQB1*0602 positivity was similarly distributed in the older individuals with insomnia (24%) as in the general population (25%). Most sleep variables were statistically indistinguishable between DQB1*0602 positive and negative subjects except that those with the allele reported that they were significantly less well rested than those without it. When sleep efficiencies were lower than 70%, DQB1*0602 positive subjects reported being less well rested at the same sleep efficiency than those without the allele. Examination of EEG during REM sleep also revealed that DQB1*0602 positive subjects had EEG shifted towards faster frequencies compared with negative subjects. Thus, DQB1*0602 positivity is associated with both a shift in EEG power spectrum to faster frequencies during REM sleep and a diminution of restedness given the same sleep quantity.

    View details for DOI 10.1016/j.psychres.2011.01.007

    View details for Web of Science ID 000290506500014

    View details for PubMedID 21292329

  • Exposure to Room Light before Bedtime Suppresses Melatonin Onset and Shortens Melatonin Duration in Humans JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Gooley, J. J., Chamberlain, K., Smith, K. A., Khalsa, S. B., Rajaratnam, S. M., Van Reen, E., Zeitzer, J. M., Czeisler, C. A., Lockley, S. W. 2011; 96 (3): E463-E472


    Millions of individuals habitually expose themselves to room light in the hours before bedtime, yet the effects of this behavior on melatonin signaling are not well recognized.We tested the hypothesis that exposure to room light in the late evening suppresses the onset of melatonin synthesis and shortens the duration of melatonin production.In a retrospective analysis, we compared daily melatonin profiles in individuals living in room light (<200 lux) vs. dim light (<3 lux).Healthy volunteers (n = 116, 18-30 yr) were recruited from the general population to participate in one of two studies.Participants lived in a General Clinical Research Center for at least five consecutive days.Individuals were exposed to room light or dim light in the 8 h preceding bedtime.Melatonin duration, onset and offset, suppression, and phase angle of entrainment were determined.Compared with dim light, exposure to room light before bedtime suppressed melatonin, resulting in a later melatonin onset in 99.0% of individuals and shortening melatonin duration by about 90 min. Also, exposure to room light during the usual hours of sleep suppressed melatonin by greater than 50% in most (85%) trials.These findings indicate that room light exerts a profound suppressive effect on melatonin levels and shortens the body's internal representation of night duration. Hence, chronically exposing oneself to electrical lighting in the late evening disrupts melatonin signaling and could therefore potentially impact sleep, thermoregulation, blood pressure, and glucose homeostasis.

    View details for DOI 10.1210/jc.2010-2098

    View details for Web of Science ID 000288020600005

    View details for PubMedID 21193540

  • Lack of Association Between COMT Polymorphisms and Apathy in Alzheimer's Disease JOURNAL OF ALZHEIMERS DISEASE David, R., Friedman, L., Mulin, E., Noda, A., Le Duff, F., Kennedy, Q., Garcia, R., Robert, P. H., Yesavage, J. A., Zeitzer, J. M. 2011; 27 (1): 155-161


    We tested the hypothesis that single nucleotide polymorphisms (SNPs) in catechol-O-methyltransferase (COMT) are associated with apathy in individuals with Alzheimer's disease (AD). We analyzed a cohort of 105 Caucasian individuals with AD (age = 79.3 ± 7.03 years; MMSE = 20.2 ± 4.4) according to the presence of apathy, as defined either by the Neuropsychiatric Inventory or the Apathy Inventory. Polymorphisms in seventeen SNPs in COMT were examined. A replication cohort consisting of 176 Caucasian AD subjects in the ADNI database was also analyzed. None of the candidate gene SNPs were significantly associated with the presence of apathy in either cohort. We did not find any SNPs in COMT that were consistently associated with apathy in individuals with AD.

    View details for DOI 10.3233/JAD-2011-110491

    View details for Web of Science ID 000296570400014

    View details for PubMedID 21785189

  • Relationship between Apathy and Sleep Disturbance in Mild and Moderate Alzheimer's Disease: An Actigraphic Study JOURNAL OF ALZHEIMERS DISEASE Mulin, E., Zeitzer, J. M., Friedman, L., Le Duff, F., Yesavage, J., Robert, P. H., David, R. 2011; 25 (1): 85-91


    Apathy is the most frequently reported neuropsychiatric symptom across all stages of Alzheimer's disease (AD). Both apathy and sleep disorders are known to have independent negative effects on the quality of life in individuals with AD. The aim of this study was to assess the relationship between apathy and sleep/wake patterns in individuals with AD using ambulatory actigraphy. One hundred and three non-institutionalized individuals with AD wore a wrist actigraph continuously over seven consecutive 24-h periods. Apathy was assessed using the Neuropsychiatric Inventory. Daytime mean motor activity (dMMA) was calculated from daytime wrist actigraphy data. Actigraphic parameters of sleep included total sleep time (TST), wake after sleep onset (WASO), time in bed (TIB), WASO normalized by TIB, sleep latency, and nighttime mean motor activity (nMMA). Among the 103 individuals with AD (aged 76.9 ± 7.2 years; MMSE = 21.4 ± 4.3), those with apathy had significantly lower dMMA, higher WASO (both raw and normalized), and spent more time in bed during the night than those without apathy. Sleep latency, nMMA and TST did not differ significantly between the two subgroups. To our knowledge, this study is the first to identify a relationship between apathy and sleep disturbance in those with mild or moderate AD: apathy was associated with increased TIB during the night and more WASO. These results suggest that AD patients with apathy have less consolidated nocturnal sleep than those without apathy.

    View details for DOI 10.3233/JAD-2011-101701

    View details for Web of Science ID 000293377700009

    View details for PubMedID 21335662

  • Effects of sleep on the cardiovascular and thermoregulatory systems: a possible role for hypocretins JOURNAL OF APPLIED PHYSIOLOGY Schwimmer, H., Stauss, H. M., Abboud, F., Nishino, S., Mignot, E., Zeitzer, J. M. 2010; 109 (4): 1053-1063


    Sleep influences the cardiovascular, endocrine, and thermoregulatory systems. Each of these systems may be affected by the activity of hypocretin (orexin)-producing neurons, which are involved in the etiology of narcolepsy. We examined sleep in male rats, either hypocretin neuron-ablated orexin/ataxin-3 transgenic (narcoleptic) rats or their wild-type littermates. We simultaneously monitored electroencephalographic and electromyographic activity, core body temperature, tail temperature, blood pressure, electrocardiographic activity, and locomotion. We analyzed the daily patterns of these variables, parsing sleep and circadian components and changes between states of sleep. We also analyzed the baroreceptor reflex. Our results show that while core temperature and heart rate are affected by both sleep and time of day, blood pressure is mostly affected by sleep. As expected, we found that both blood pressure and heart rate were acutely affected by sleep state transitions in both genotypes. Interestingly, hypocretin neuron-ablated rats have significantly lower systolic and diastolic blood pressure during all sleep stages (non-rapid eye movement, rapid eye movement) and while awake (quiet, active). Thus, while hypocretins are critical for the normal temporal structure of sleep and wakefulness, they also appear to be important in regulating baseline blood pressure and possibly in modulating the effects of sleep on blood pressure.

    View details for DOI 10.1152/japplphysiol.00516.2010

    View details for Web of Science ID 000285344900016

    View details for PubMedID 20705949

  • Sex Differences in Phase Angle of Entrainment and Melatonin Amplitude in Humans JOURNAL OF BIOLOGICAL RHYTHMS Cain, S. W., Dennison, C. F., Zeitzer, J. M., Guzik, A. M., Khalsa, S. B., Santhi, N., Schoen, M. W., Czeisler, C. A., Duffy, J. F. 2010; 25 (4): 288-296


    Studies of sex differences in the timing of human circadian rhythms have reported conflicting results. This may be because the studies conducted to date have not controlled for the masking effects of the rest activity cycle on the circadian rhythms being assessed. In the present analysis of data collected under controlled conditions, we examined sex differences in the timing of circadian rhythms while minimizing masking from behavioral and environmental factors using a constant routine (CR) protocol. All participants (28 women and 28 men paired by habitual wake time; age range, 18 30 years) maintained a regular self selected sleep wake schedule at home prior to the study. After 3 baseline days in the laboratory, participants began a CR. Women were found to have a significantly higher melatonin amplitude and lower temperature amplitude than men. While sleep timing was the same between the 2 groups, the timing of the circadian rhythms of core body temperature and pineal melatonin secretion was earlier relative to sleep time in women as compared to men. Sleep therefore occurred at a later biological time for women than men, despite being at the same clock time. Given that sleep propensity and structure vary with circadian phase and are impacted by circulating melatonin, these findings may have important implications for understanding sex differences in sleep timing and duration, diurnal preference, and the prevalence of sleep disorders such as insomnia.

    View details for DOI 10.1177/0748730410374943

    View details for Web of Science ID 000280610000006

    View details for PubMedID 20679498

  • Preliminary evidence that plasma oxytocin levels are elevated in major depression PSYCHIATRY RESEARCH Parker, K. J., Kenna, H. A., Zeitzer, J. M., Keller, J., Blasey, C. M., Amico, J. A., Schatzberg, A. F. 2010; 178 (2): 359-362


    It is well established that the neuropeptide oxytocin (OT) is involved in regulating social behavior, anxiety, and hypothalamic-pituitary-adrenal (HPA) axis physiology in mammals. Because individuals with major depression often exhibit functional irregularities in these measures, we test in this pilot study whether depressed subjects (n=11) exhibit dysregulated OT biology compared to healthy control subjects (n=19). Subjects were hospitalized overnight and blood samples were collected hourly between 1800 and 0900h. Plasma levels of OT, the closely related neuropeptide argine-vasopressin (AVP), and cortisol were quantified. Results indicated that depressed subjects exhibit increased OT levels compared to healthy control subjects, and this difference is most apparent during the nocturnal peak. No depression-related differences in AVP or cortisol levels were discerned. This depression-related elevation in plasma OT levels is consistent with reports of increased hypothalamic OT-expressing neurons and OT mRNA in depressed patients. This present finding is likewise consistent with the hypothesis that dysregulated OT biology may be a biomarker of the emotional distress and impaired social relationships which characterize major depression. Additional research is required to elucidate the role of OT in the pathophysiology of this psychiatric disorder.

    View details for DOI 10.1016/j.psychres.2009.09.017

    View details for Web of Science ID 000279988900025

    View details for PubMedID 20494448

    View details for PubMedCentralID PMC2902664

  • Non-pharmacologic management of sleep disturbance in Alzheimer's disease JOURNAL OF NUTRITION HEALTH & AGING David, R., Zeitzer, J., Friedman, L., Noda, A., O'Hara, R., Robert, P., Yesavage, J. A. 2010; 14 (3): 203-206


    Sleep and wake in Alzheimer's disease (AD) are often fragmented as manifested by bouts of wakefulness at night and napping during the day. Management of sleep disturbances in AD is important because of their negative impact on both patients and caregivers. Pharmacological treatments, mainly sedative-hypnotics and antipsychotics, are often used but can be associated with significant adverse effects. Non-pharmacological treatments represent a beneficial alternative approach to the management of sleep disturbances in AD since they are associated with fewer adverse effects and their efficacy can be sustained after treatment has been completed. The aim of this article is to review non-pharmacological treatments, such as sleep hygiene, sleep restriction therapy (SRT), cognitive behavioral therapy (CBT), light therapy, and continuous positive airway pressure (CPAP), for the management of sleep/wake disturbances in AD.

    View details for DOI 10.1007/s12603-010-0050-9

    View details for Web of Science ID 000276527000006

    View details for PubMedID 20191254

  • Modafinil and gamma-hydroxybutyrate have sleep state-specific pharmacological actions on hypocretin-1 physiology in a primate model of human sleep BEHAVIOURAL PHARMACOLOGY Zeitzer, J. M., Buckmaster, C. L., Landoltd, H., Lyons, D. M., Mignot, E. 2009; 20 (7): 643-652


    Hypocretin-1 is a hypothalamic neuropeptide that is important in the regulation of wake and the lack of which results in the sleep disorder narcolepsy. Using a monkey that has consolidated wake akin to humans, we examined pharmacological manipulation of sleep and wake and its effects on hypocretin physiology. Monkeys were given the sleep-inducing γ-hydroxybutyrate (GHB) and the wake-inducing modafinil both in the morning and in the evening. Cerebrospinal fluid hypocretin-1 concentrations changed significantly in response to the drugs only when accompanied by a behavioral change (GHB-induced sleep in the morning or modafinil-induced wake in the evening). We also found that there was a large (180-fold) interindividual variation in GHB pharmacokinetics that explains variability in sleep induction in response to the drug. Our data indicate that the neurochemical concomitants of sleep and wake are capable of changing the physiological output of hypocretin neurons. Sleep independent of circadian timing is capable of decreasing cerebrospinal fluid hypocretin-1 concentrations. Furthermore, hypocretin neurons do not seem to respond to an 'effort' to remain awake, but rather keep track of time spent awake as a wake-promoting counterbalance to extended wakefulness.

    View details for DOI 10.1097/FBP.0b013e328331b9db

    View details for Web of Science ID 000270483300010

    View details for PubMedID 19752724

  • Elevated Anti-Streptococcal Antibodies in Patients with Recent Narcolepsy Onset SLEEP Aran, A., Lin, L., Nevsimalova, S., Plazzi, G., Hong, S. C., Weiner, K., Zeitzer, J., Mignot, E. 2009; 32 (8): 979-983


    Narcolepsy-cataplexy has long been thought to have an autoimmune origin. Although susceptibility to narcolepsy, like many autoimmune conditions, is largely genetically determined, environmental factors are involved based on the high discordance rate (approximately 75%) of monozygotic twins. This study evaluated whether Streptococcus pyogenes and Helicobacter pylori infections are triggers for narcolepsy.Retrospective, case-control.Sleep centers of general hospitals.200 patients with narcolepsy/hypocretin deficiency, with a primary focus on recent onset cases and 200 age-matched healthy controls. All patients were DQB1*0602 positive with low CSF hypocretin-1 or had clear-cut cataplexy.Participants were tested for markers of immune response to beta hemolytic streptococcus (anti-streptolysin O [ASO]; anti DNAse B [ADB]) and Helicobacter pylori [Anti Hp IgG], two bacterial infections known to trigger autoimmunity. A general inflammatory marker, C-reactive protein (CRP), was also studied. When compared to controls, ASO and ADB titers were highest close to narcolepsy onset, and decreased with disease duration. For example, ASO > or = 200 IU (ADB > or = 480 IU) were found in 51% (45%) of 67 patients within 3 years of onset, compared to 19% (17%) of 67 age matched controls (OR = 4.3 [OR = 4.1], P < 0.0005) or 20% (15%) of 69 patients with long-standing disease (OR = 4.0 [OR = 4.8], P < 0.0005]. CRP (mean values) and Anti Hp IgG (% positive) did not differ from controls.Streptococcal infections are probably a significant environmental trigger for narcolepsy.

    View details for Web of Science ID 000268557600004

    View details for PubMedID 19725248

  • Scheduled Bright Light for Treatment of Insomnia in Older Adults JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Friedman, L., Zeitzer, J. M., Kushida, C., Zhdanova, I., Noda, A., Lee, T., Schneider, B., Guilleminault, C., Sheikh, J., Yesavage, J. A. 2009; 57 (3): 441-452


    To determine whether bright light can improve sleep in older individuals with insomnia.Single-blind, placebo-controlled, 12-week, parallel-group randomized design comparing four treatment groups representing a factorial combination of two lighting conditions and two times of light administration.At-home light treatment; eight office therapy sessions.Thirty-six women and fifteen men (aged 63.6+/-7.1) meeting primary insomnia criteria recruited from the community.A 12-week program of sleep hygiene and exposure to bright ( approximately 4,000 lux) or dim light ( approximately 65 lux) scheduled daily in the morning or evening for 45 minutes.Within-group changes were observed for subjective (sleep logs, questionnaires) and objective (actigraphy, polysomnography) sleep measures after morning or evening bright light.Within-group changes for subjective sleep measures after morning or evening bright light were not significantly different from those observed after exposure to scheduled dim light. Objective sleep changes (actigraphy, polysomnography) after treatment were not significantly different between the bright and dim light groups. Scheduled light exposure was able to shift the circadian phase predictably but was unrelated to changes in objective or subjective sleep measures. A polymorphism in CLOCK predicted morningness but did not moderate the effects of light on sleep. The phase angle between the circadian system (melatonin midpoint) and sleep (darkness) predicted the magnitude of phase delays, but not phase advances, engendered by bright light.Except for one subjective measure, scheduled morning or evening bright light effects were not different from those of scheduled dim light. Thus, support was not found for bright light treatment of older individuals with primary insomnia.

    View details for DOI 10.1111/j.1532-5415.2008.02164.x

    View details for Web of Science ID 000263859600008

    View details for PubMedID 19187411

    View details for PubMedCentralID PMC2743069

  • Sleep apnea, apolipoprotein epsilon 4 allele, and TBI: Mechanism for cognitive dysfunction and development of dementia JOURNAL OF REHABILITATION RESEARCH AND DEVELOPMENT O'Hara, R., Luzon, A., Hubbard, J., Zeitzer, J. M. 2009; 46 (6): 837-850


    Sleep apnea is prevalent among patients with traumatic brain injuries (TBIs), and initial studies suggest it is associated with cognitive impairments in these patients. Recent studies found that the apolipoprotein epsilon 4 (APOE epsilon 4) allele increases the risk for sleep disordered breathing, particularly sleep apnea. The APOE epsilon 4 allele is associated with cognitive decline and the development of dementia in the general population as well as in patients with TBI. These findings raise the question of whether patients with TBI who are APOE epsilon 4 allele carriers are more vulnerable to the negative effects of sleep apnea on their cognitive functioning. While few treatments are available for cognitive impairment, highly effective treatments are available for sleep apnea. Here we review these different lines of evidence, making a case that the interactive effects of sleep apnea and the APOE epsilon 4 allele represent an important mechanism by which patients with TBI may develop a range of cognitive and neurobehavioral impairments. Increased understanding of the relationships among sleep apnea, the APOE epsilon 4 allele, and cognition could improve our ability to ameliorate one significant source of cognitive impairment and risk for dementia associated with TBI.

    View details for DOI 10.1682/JRRD.2008.10.0140

    View details for Web of Science ID 000272638100015

    View details for PubMedID 20104407

  • HLA DQB1*0602 IS ASSOCIATED WITH SLEEP PERCEPTION IN OLDER INDIVIDUALS WITH INSOMNIA 23rd Annual Meeting of the Associated-Professional-Sleep-Societies (APSS) Zeitzer, J., Grove, M. E., Mignot, E., Yesavage, J. A., Friedman, L. AMER ACAD SLEEP MEDICINE. 2009: A262–A262
  • Neuropsychiatric diagnosis and management of chronic sequelae of war-related mild to moderate traumatic brain injury JOURNAL OF REHABILITATION RESEARCH AND DEVELOPMENT Halbauer, J. D., Ashford, J. W., Zeitzer, J. M., Adamson, M. M., Lew, H. L., Yesavage, J. A. 2009; 46 (6): 757-795


    Soldiers with a traumatic brain injury (TBI) present with an array of neuropsychiatric symptoms that can be grouped into nosological clusters: (1) cognitive dysfunctions: difficulties in memory, attention, language, visuospatial cognition, sensory-motor integration, affect recognition, and/or executive function typically associated with neocortical damage; (2) neurobehavioral disorders: mood, affect, anxiety, posttraumatic stress, and psychosis, as well as agitation, sleep problems, and libido loss, that may have been caused by damage to the cortex, limbic system, and/or brain stem monoaminergic projection systems; (3) somatosensory disruptions: impaired smell, vision, hearing, equilibrium, taste, and somatosensory perception frequently caused by trauma to the sensory organs or their projections through the brain stem to central processing systems; (4) somatic symptoms: headache and chronic pain; and (5) substance dependence. TBI-related cognitive impairment is common in veterans who have served in recent conflicts in the Middle East and is often related to blasts from improvised explosive devices. Although neurobehavioral disorders such as depression and posttraumatic stress disorder commonly occur after combat, the presentation of such disorders in those with head injury may pass undetected with use of current diagnostic criteria and neuropsychological instruments. With a multidimensional approach (such as the biopsychosocial model) applied to each symptom cluster, psychological, occupational, and social dysfunction can be delineated and managed.

    View details for DOI 10.1682/JRRD.2008.08.0119

    View details for Web of Science ID 000272638100010

    View details for PubMedID 20104402

  • Insomnia in the context of traumatic brain injury JOURNAL OF REHABILITATION RESEARCH AND DEVELOPMENT Zeitzer, J. M., Friedman, L., O'Hara, R. 2009; 46 (6): 827-835


    Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in the United States. One of the most common comorbidities of TBI is the disruption of normal sleep. While often viewed as a nuisance symptom, sleep disruption can delay TBI recovery and negatively affect many of the psychological (e.g., anxiety, depression) and neuromuscular (e.g., pain) sequelae of TBI, decreasing quality of life. Treatment of sleep disruption in the context of TBI is complicated by issues of an altered neuronal milieu, polypharmacy, and the complex relationship between the various comorbidities often found in patients with TBI. Given the growing number of veterans returning from combat with TBI and the elevated risk of comorbid disrupted sleep, both caused by and independent of TBI, a comprehensive review of sleep disruption and its treatment is of great relevance to the Department of Veterans Affairs.

    View details for DOI 10.1682/JRRD.2008.08.0099

    View details for Web of Science ID 000272638100014

    View details for PubMedID 20104406

  • Vagal regulation, cortisol, and sleep disruption in women with metastatic breast cancer. Journal of clinical sleep medicine Palesh, O., Zeitzer, J. M., Conrad, A., Giese-Davis, J., Mustian, K. M., Popek, V., Nga, K., Spiegel, D. 2008; 4 (5): 441-449


    To determine the relationship between hypothalamic pituitary axis (HPA) dysregulation, vagal functioning, and sleep problems in women with metastatic breast cancer.Sleep was assessed by means of questionnaires and wrist actigraphy for 3 consecutive nights. The ambulatory, diurnal variation in salivary cortisol levels was measured at 5 time points over 2 days. Vagal regulation was assessed via respiratory sinus arrhythmia (RSA(TF)) during the Trier Social Stress Task.Ninety-nine women (54.6 +/- 9.62 years) with metastatic breast cancer.Longer nocturnal wake episodes (r = 0.21, p = 0.04, N=91) were associated with a flatter diurnal cortisol slope. Sleep disruption was also associated with diminished RSA(TF). Higher RSA baseline scores were significantly correlated with higher sleep efficiency (r = 0.39, p = 0.001, N=68) and correspondingly lower levels of interrupted sleep (waking after sleep onset, WASO; r = -0.38, p = 0.002, N=68), lower average length of nocturnal wake episodes (r = -0.43, p < 0.001, N=68), and a lower self-reported number of hours of sleep during a typical night (r = -0.27, p = 0.02, N=72). Higher RSA AUC was significantly related to higher sleep efficiency (r = 0.45, p < 0.001, N=64), and a correspondingly lower number of wake episodes (r = -0.27, p = 0.04, N=64), lower WASO (r = -0.40, p = 0.001, N=64), and with lower average length of nocturnal wake episodes (r = -0.41, p = 0.001, N=64). While demographics, disease severity, and psychological variables all explained some portion of the development of sleep disruption, 4 of the 6 sleep parameters examined (sleep efficiency, WASO, mean number of waking episodes, average length of waking episode) were best explained by RSA.These data provide preliminary evidence for an association between disrupted nocturnal sleep and reduced RSA the subsequent day, confirming an association between disrupted nocturnal sleep and flattened diurnal cortisol rhythm in women with metastatic breast cancer. They suggest that the stress-buffering effects of sleep may be associated with improved parasympathetic tone and normalized cortisol patterns during the day.

    View details for PubMedID 18853702

  • CSF hypocretin-1 assessment in sleep and neurological disorders LANCET NEUROLOGY Bourgin, P., Zeitzer, J. M., Mignot, E. 2008; 7 (7): 649-662


    Concentrations of CSF hypocretin-1 (formerly orexin A) have been measured in many patients with sleep or neurological conditions. Low CSF hypocretin-1 is most predictive of narcolepsy in patients positive for HLA allele DQB1*0602, most of whom have cataplexy. By contrast, the diagnostic significance of low CSF hypocretin-1 is unclear in the presence of acute CNS inflammation or trauma. The clinical usefulness of CSF testing in hypersomnia that is symptomatic of a neurological disorder remains to be evaluated. Determination of CSF hypocretin-1 concentration to diagnose narcolepsy might be most useful in ambulatory patients with cataplexy but with a normal multiple sleep latency test (MSLT) result, or if MSLT is not interpretable, conclusive, or feasible. Because 98% of patients with hypocretin-1 deficiency are positive for HLA DQB1*0602, we suggest that HLA typing is a useful screen before lumbar puncture. Although hypocretin-1 deficiency in narcolepsy might have therapeutic relevance, additional research is needed in this area.

    View details for Web of Science ID 000257213600021

    View details for PubMedID 18565458

  • Kleine-Levin syndrome: A systematic study of 108 patients ANNALS OF NEUROLOGY Arnulf, I., Lin, L., Gadoth, N., File, J., Lecendreux, M., Franco, P., Zeitzer, J., Lo, B., Faraco, J. H., Mignot, E. 2008; 63 (4): 482-493


    Kleine-Levin syndrome is a rare disorder characterized by relapsing-remitting episodes of hypersomnia, cognitive disturbances, and behavioral disturbances, such as hyperphagia and hypersexuality.We collected detailed clinical data and blood samples on 108 patients, 79 parent pairs, and 108 matched control subjects. We measured biological markers and typed human leukocyte antigen genes DR and DQ.Novel predisposing factors were identified including increased birth and developmental problems (odds ratio, 6.5). Jewish heritage was overrepresented, and five multiplex families were identified. Human leukocyte antigen typing was unremarkable. Patients were 78% male (mean age at onset, 15.7 +/- 6.0 years), averaged 19 episodes of 13 days, and were incapacitated 8 months over 14 years. The disease course was longer in men, in patients with hypersexuality, and when onset was after age 20. During episodes, all patients had hypersomnia, cognitive impairment, and derealization; 66% had megaphagia; 53% reported hypersexuality (principally men); and 53% reported a depressed mood (predominantly women). Patients were remarkably similar to control subjects between episodes regarding sleep, mood, and eating attitude, but had increased body mass index. We found marginal efficacy for amantadine and mood stabilizers, but found no increased family history for neuropsychiatric disorders.The similarity of the clinical and demographic features across studies strongly suggests that Kleine-Levin syndrome is a genuine disease entity. Familial clustering and increased prevalence in the Jewish population support a role for a major genetic susceptibility factor. Considering the inefficacy of available treatments, we propose that disease management should primarily be supportive and educational.

    View details for DOI 10.1002/ana.21333

    View details for Web of Science ID 000255454400011

    View details for PubMedID 18438947

  • Vagal Regulation, Cortisol, and Sleep Disruption in Women with Metastatic Breast Cancer JOURNAL OF CLINICAL SLEEP MEDICINE Palesh, O., Zeitzer, J. M., Conrad, A., Giese-Davis, J., Mustian, K. M., Popek, V., Nga, K., Spiegel, D. 2008; 4 (5): 441-449
  • Preliminary evidence that hippocampal volumes in monkeys predict stress levels of adrenocorticotropic hormone BIOLOGICAL PSYCHIATRY Lyons, D. M., Parker, K. J., Zeitzer, J. M., Buckmaster, C. L., Schatzberg, A. F. 2007; 62 (10): 1171-1174


    Hippocampal volumes previously determined in monkeys by magnetic resonance imaging are used to test the hypothesis that small hippocampi predict increased stress levels of adrenocorticotropic hormone (ACTH).Plasma ACTH levels were measured after restraint stress in 19 male monkeys pretreated with saline or hydrocortisone. Monkeys were then randomized to an undisturbed control condition or intermittent social separations followed by new pair formations. After 17 months of exposure to the intermittent social manipulations, restraint stress tests were repeated to determine test/retest correlations.Individual differences in postrestraint stress ACTH levels over the 17-month test/retest interval were remarkably consistent for the saline (r(s) = .82, p = .0004) and hydrocortisone (r(s) = .78, p = .001) pretreatments. Social manipulations did not affect postrestraint stress ACTH levels, but monkeys with smaller hippocampal volumes responded to restraint after saline pretreatment with greater increases in ACTH levels with total brain volume variation controlled as a statistical covariate (beta = -.58, p = .031). Monkeys with smaller hippocampal volumes also responded with diminished sensitivity to glucocorticoid feedback determined by greater postrestraint ACTH levels after pretreatment with hydrocortisone (beta = -.68, p = .010).These findings support clinical reports that small hippocampi may be a risk factor for impaired regulation of the hypothalamic-pituitary-adrenal axis in humans with stress-related psychiatric disorders.

    View details for DOI 10.1016/i.biopsych.2007.03.012

    View details for Web of Science ID 000250905800015

    View details for PubMedID 17573043

    View details for PubMedCentralID PMC2129091

  • Plasma melatonin rhythms in young and older humans during sleep, sleep deprivation, and wake SLEEP Zeitzer, J. M., Duffy, J. F., Lockley, S. W., Dijk, D., Czeisler, C. A. 2007; 30 (11): 1437-1443


    To determine the effects of sleep and sleep deprivation on plasma melatonin concentrations in humans and whether these effects are age-dependent.At least 2 weeks of regular at-home, sleep/wake schedule followed by 3 baseline days in the laboratory and at least one constant routine (sleep deprivation).General Clinical Research Center (GCRC), Brigham and Women's Hospital, Boston, MA.In Study 1, one group (<10 lux when awake) of 19 young men (18-30 y) plus a second group (<2 lux when awake) of 15 young men (20-28 y) and 10 young women (19-27 y); in Study 2, 90 young men (18-30 y), 18 older women (65-81 y), and 11 older men (64-75 y). All participants were in good health, as determined by medical and psychological screening.One to three constant routines with interspersed inversion of the sleep/wake cycle in those with multiple constant routines.Examination of plasma melatonin concentrations and core body temperature. Study 1. There was a small, but significant effect of sleep deprivation of up to 50 hours on melatonin concentrations (increase of 9.81 +/- 3.73%, P <0.05, compared to normally timed melatonin). There was also an effect of circadian phase angle with the prior sleep episode, such that if melatonin onset occurred <8 hours after wake time, the amplitude was significantly lower (22.4% +/- 4.79%, P <0.001). Study 2. In comparing melatonin concentrations during sleep to the same hours during constant wakefulness, in young men, melatonin amplitude was 6.7% +/- 2.1% higher(P <0.001) during the sleep episode. In older men, melatonin amplitude was 37.0% +/- 12.5% lower (P <0.05) during the sleep episode and in older women, melatonin amplitude was non-significantly 10.9% +/- 8.38% lower (P = 0.13) during the sleep episode.Both sleep and sleep deprivation likely influence melatonin amplitude, and the effect of sleep on melatonin appears to be age dependent.

    View details for Web of Science ID 000250724600005

    View details for PubMedID 18041478

  • Increasing length of wakefulness and modulation of hypocretin-1 in the wake-consolidated squirrel monkey AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Zeitzer, J. M., Buckmaster, C. L., Lyons, D. M., Mignot, E. 2007; 293 (4): R1736-R1742


    The neuropeptides hypocretins (orexins), the loss of which results in the sleep disorder narcolepsy, are hypothesized to be involved in the consolidation of wakefulness and have been proposed to be part of the circadian-driven alertness signal. To elucidate the role of hypocretins in the consolidation of human wakefulness we examined the effect of wake extension on hypocretin-1 in squirrel monkeys, primates that consolidate wakefulness during the daytime as do humans. Wake was extended up to 7 h with hypocretin-1, cortisol, ghrelin, leptin, locomotion, and feeding, all being assayed. Hypocretin-1 (P < 0.01), cortisol (P < 0.001), and locomotion (P < 0.005) all increased with sleep deprivation, while ghrelin (P = 0.79) and leptin (P = 1.00) did not change with sleep deprivation. Using cross-correlation and multivariate modeling of these potential covariates along with homeostatic pressure (a measure of time awake/asleep), we found that time of day and homeostatic pressure together explained 44% of the variance in the hypocretin-1 data (P < 0.001), while cortisol did not significantly contribute to the overall hypocretin-1 variance. Locomotion during the daytime, but not during the nighttime, helped explain < 5% of the hypocretin-1 variance (P < 0.05). These data are consistent with earlier evidence indicating that in the squirrel monkey hypocretin-1 is mainly regulated by circadian inputs and homeostatic sleep pressure. Concomitants of wakefulness that affect hypocretin-1 in polyphasic species, such as locomotion, food intake, and food deprivation, likely have a more minor role in monophasic species, such as humans.

    View details for DOI 10.1152/ajpregu.00460.2007

    View details for Web of Science ID 000250088000033

    View details for PubMedID 17686881

  • A physiologically based mathematical model of melatonin including ocular light suppression and interactions with the circadian pacemaker JOURNAL OF PINEAL RESEARCH St Hilaire, M. A., Gronfier, C., Zeitzer, J. M., Klerman, E. B. 2007; 43 (3): 294-304


    The rhythm of plasma melatonin concentration is currently the most accurate marker of the endogenous human circadian pacemaker. A number of methods exist to estimate circadian phase and amplitude from the observed melatonin rhythm. However, almost all these methods are limited because they depend on the shape and amplitude of the melatonin pulse, which vary among individuals and can be affected by environmental influences, especially light. Furthermore, these methods are not based on the underlying known physiology of melatonin secretion and clearance, and therefore cannot accurately quantify changes in secretion and clearance observed under different experimental conditions. A published physiologically-based mathematical model of plasma melatonin can estimate synthesis onset and offset of melatonin under dim light conditions. We amended this model to include the known effect of melatonin suppression by ocular light exposure and to include a new compartment to model salivary melatonin concentration, which is widely used in clinical settings to determine circadian phase. This updated model has been incorporated into an existing mathematical model of the human circadian pacemaker and can be used to simulate experimental protocols under a number of conditions.

    View details for DOI 10.1111/j.1600-079X.2007.00477.x

    View details for Web of Science ID 000249425400012

    View details for PubMedID 17803528

  • Sleep/wake fragmentation disrupts metabolism in a mouse model of narcolepsy JOURNAL OF PHYSIOLOGY-LONDON Zhang, S., Zeitzer, J. M., Sakurai, T., Nishino, S., Mignot, E. 2007; 581 (2): 649-663


    Recent population studies have identified important interrelationships between sleep duration and body weight regulation. The hypothalamic hypocretin/orexin neuropeptide system is able to influence each of these. Disruption of the hypocretin system, such as occurs in narcolepsy, leads to a disruption of sleep and is often associated with increased body mass index. We examined the potential interrelationship between the hypocretin system, metabolism and sleep by measuring locomotion, feeding, drinking, body temperature, sleep/wake and energy metabolism in a mouse model of narcolepsy (ataxin-ablation of hypocretin-expressing neurons). We found that locomotion, feeding, drinking and energy expenditure were significantly reduced in the narcoleptic mice. These mice also exhibited severe sleep/wake fragmentation. Upon awakening, transgenic and control mice displayed a similar rate of increase in locomotion and food/water intake with time. A lack of long wake episodes partially or entirely explains observed differences in overall locomotion, feeding and drinking in these transgenic mice. Like other parameters, energy expenditure also rose and fell depending on the sleep/wake status. Unlike other parameters, however, energy expenditure in control mice increased upon awakening at a greater rate than in the narcoleptic mice. We conclude that the profound sleep/wake fragmentation is a leading cause of the reduced locomotion, feeding, drinking and energy expenditure in the narcoleptic mice under unperturbed conditions. We also identify an intrinsic role of the hypocretin system in energy expenditure that may not be dependent on sleep/wake regulation, locomotion, or food intake. This investigation illustrates the need for coordinated study of multiple phenotypes in mouse models with altered sleep/wake patterns.

    View details for DOI 10.1113/jphysiol.2007.129510

    View details for Web of Science ID 000246756000022

    View details for PubMedID 17379635

  • Decreased sensitivity to phase-delaying effects of moderate intensity light in older subjects NEUROBIOLOGY OF AGING Duffy, J. F., Zeitzer, J. M., Czeisler, C. A. 2007; 28 (5): 799-807


    Aging is associated with a change in the relationship between the timing of sleep and circadian rhythms, such that the rhythms occur later with respect to sleep than in younger adults. To investigate whether a difference in the phase-delaying response to evening light contributes to this, we conducted a 9-day inpatient study in 10 healthy older (> or =65 y.o.) subjects. We assessed circadian phase in a constant routine, exposed each subject to a 6.5h broad-spectrum light stimulus beginning in the early biological night, and reassessed circadian phase. The stimuli spanned a range from very dim (approximately 2 lx) to very bright (approximately 8000 lx) indoor light. We found a significant dose-response relationship between illuminance and the phase shift of the melatonin rhythm, with evidence that sensitivity, but not the maximal response to light, differed from that of younger adults. These findings suggest an age-related reduction in the phase-delaying response to moderate light levels. However, our findings alone do not explain the altered phase relationship between sleep and circadian rhythms associated with aging.

    View details for DOI 10.1016/j.neurobiolaging.2006.03.005

    View details for Web of Science ID 000245109700018

    View details for PubMedID 16621166

  • Normal cerebrospinal fluid levels of hypocretin-1 (orexin A) in patients with fibromyalgia syndrome SLEEP MEDICINE Taiwo, O. B., Russell, I. J., Mignot, E., Lin, L., Michalek, J. E., Haynes, W., Xiao, Y., Zeiter, J. M., Larson, A. A. 2007; 8 (3): 260-265


    The hypothalamic neuropeptide hypocretin (orexin) modulates sleep-wake, feeding and endocrine functions. Cerebrospinal fluid (CSF) hypocretin-1 (Hcrt-1) concentrations are low in patients with narcolepsy-cataplexy, a sleep disorder characterized by hypersomnolence and rapid eye movement (REM) sleep abnormalities.We determined CSF Hcrt-1 concentrations of patients with the fibromyalgia syndrome (FMS), a condition characterized by fatigue, insomnia and in some cases daytime hypersomnolence.Basal CSF levels of Hcrt-1 in FMS did not differ from those in healthy normal controls.These findings suggest that abnormally low Hcrt-1 is not a likely cause of fatigue in FMS.

    View details for DOI 10.1016/j.sleep.2006.08.015

    View details for Web of Science ID 000246343100010

    View details for PubMedID 17369087

  • In Alzheimer disease, increased wake fragmentation found in those with lower hypocretin-1 NEUROLOGY Friedman, L. F., Zeitzer, J. M., Lin, L., Hoff, D., Mignot, E., Peskind, E. R., Yesavage, J. A. 2007; 68 (10): 793-794

    View details for Web of Science ID 000244679900020

    View details for PubMedID 17339595

  • Hypocretin-1 is inversely associated with wake fragmentation in Alzheimer's disease 21st Annual Meeting of the American-Professional-Sleep-Societies Zeitzer, J., Friedman, L., Lin, L., Mignot, E., Peskind, E., Yesavage, J. AMER ACAD SLEEP MEDICINE. 2007: A302–A302
  • The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions TRENDS IN PHARMACOLOGICAL SCIENCES Zeitzer, J. M., Nishin, S., Mignot, E. 2006; 27 (7): 368-374


    Narcolepsy is characterized by excessive daytime sleepiness, cataplexy and other manifestations of dissociated rapid eye movement sleep. Narcolepsy is typically treated with amphetamine-like stimulants (sleepiness) and antidepressants (cataplexy). Newer compounds, such as modafinil (non-amphetamine wake-promoting compound for excessive daytime sleepiness) and sodium oxybate (short-acting sedative for fragmented nighttime sleep, cataplexy, excessive daytime sleepiness), are increasingly used. Recent discoveries indicate that the major pathophysiology of human narcolepsy is the loss of lateral hypothalamic neurons that produce the neuropeptide hypocretin (orexin). Approximately 90% of people diagnosed as having narcolepsy with cataplexy are hypocretin ligand deficient. This has led to the development of new diagnostic tests (cerebrospinal fluid hypocretin-1 measurements). Hypocretin receptor agonists are likely to be ideal therapeutic options for hypocretin-deficient narcolepsy but such compounds are still not available in humans.

    View details for DOI 10.1016/

    View details for Web of Science ID 000239368900005

    View details for PubMedID 16766052

  • Extracellular adenosine in the human brain during sleep and sleep deprivation: An in vivo microdialysis study SLEEP Zeitzer, J. M., Morales-Villagran, A., Maidment, N. T., Behnke, E. J., Ackerson, L. C., Lopez-Rodriguez, F., Fried, I., Engel, J., Wilson, C. L. 2006; 29 (4): 455-461


    To examine the pattern of extracellular adenosine in the human brain during sleep deprivation, sleep, and normal wake.Following recovery from implantation of clinical depth electrodes, epilepsy patients remained awake for 40 continuous hours, followed by a recovery sleep episode.Neurology ward at UCLA Medical Center.Seven male epilepsy patients undergoing depth electrode localization of pharmacologically refractory seizures.All subjects were implanted with depth electrodes, a subset of which were customized to contain microdialysis probes. Microdialysis samples were collected during normal sleep, sleep deprivation, and recovery sleep from human amygdalae (n = 8), hippocampus (n = 1), and cortex (n = 1).In none of the probes did we observe an increase in extracellular adenosine during the sleep deprivation. There was a significant, though very small, diurnal oscillation (2.5%) in 5 of the 8 amygdalae. There was no effect of epileptogenicity on the pattern of extracellular adenosine.Our observations, along with those in animal studies, indicate that the role of extracellular adenosine in regulating sleep pressure is not a global brain phenomenon but is likely limited to specific basal forebrain areas. Thus, if energy homeostasis is a function of sleep, an increased rate of adenosine release into the extracellular milieu of the amygdala, cortex, or hippocampus is unlikely to be a marker of such a process.

    View details for Web of Science ID 000237061300009

    View details for PubMedID 16676778

  • Reduced sleep efficiency in cervical spinal cord injury; association with abolished night time melatonin secretion SPINAL CORD Scheer, F. A., Zeitzer, J. M., Ayas, N. T., Brown, R., Czeisler, C. A., Shea, S. A. 2006; 44 (2): 78-81


    Case-controlled preliminary observational study.Melatonin is usually secreted only at night and may influence sleep. We previously found that complete cervical spinal cord injury (SCI) interrupts the neural pathway required for melatonin secretion. Thus, we investigated whether the absence of night time melatonin in cervical SCI leads to sleep disturbances.General Clinical Research Center, Brigham and Women's Hospital, Boston, USA.In an ancillary analysis of data collected in a prior study, we assessed the sleep patterns of three subjects with cervical SCI plus absence of nocturnal melatonin (SCI levels: C4A, C6A, C6/7A) and two control patients with thoracic SCI plus normal melatonin rhythms (SCI levels: T4A, T5A). We also compared those results to the sleep patterns of 10 healthy control subjects.The subjects with cervical SCI had significantly lower sleep efficiency (median 83%) than the control subjects with thoracic SCI (93%). The sleep efficiency of subjects with thoracic SCI was not different from that of healthy control subjects (94%). There was no difference in the proportion of the different sleep stages, although there was a significantly increased REM-onset latency in subjects with cervical SCI (220 min) as compared to subjects with thoracic SCI (34 min). The diminished sleep in cervical SCI was not associated with sleep apnea or medication use.We found that cervical SCI is associated with decreased sleep quality. A larger study is required to confirm these findings. If confirmed, the absence of night time melatonin in cervical SCI may help explain their sleep disturbances, raising the possibility that melatonin replacement therapy could help normalize sleep in this group.

    View details for DOI 10.1038/

    View details for Web of Science ID 000235068600002

    View details for PubMedID 16130027

  • Kleine-Levin syndrome: a systematic review of 186 cases in the literature BRAIN Arnulf, I., Zeitzer, J. M., File, J., Farber, N., Mignot, E. 2005; 128: 2763-2776


    Kleine-Levin syndrome (KLS) is a rare disorder with symptoms that include periodic hypersomnia, cognitive and behavioural disturbances. Large series of patients are lacking. In order to report on various KLS symptoms, identify risk factors and analyse treatment response, we performed a systematic review of 195 articles, written in English and non-English languages, which are available on Medline dating from 1962 to 2004. Doubtful or duplicate cases, case series without individual details and reviews (n = 56 articles) were excluded. In addition, the details of 186 patients from 139 articles were compiled. Primary KLS cases (n = 168) were found mostly in men (68%) and occurred sporadically worldwide. The median age of onset was 15 years (range 4-82 years, 81% during the second decade) and the syndrome lasted 8 years, with seven episodes of 10 days, recurring every 3.5 months (median values) with the disease lasting longer in women and in patients with less frequent episodes during the first year. It was precipitated most frequently by infections (38.2%), head trauma (9%), or alcohol consumption (5.4%). Common symptoms were hypersomnia (100%), cognitive changes (96%, including a specific feeling of derealization), eating disturbances (80%), hypersexuality (43%), compulsions (29%), and depressed mood (48%). In 75 treated patients (213 trials), somnolence decreased using stimulants (mainly amphetamines) in 40% of cases, while neuroleptics and antidepressants were of poor benefit. Only lithium (but not carbamazepine or other antiepileptics) had a higher reported response rate (41%) for stopping relapses when compared to medical abstention (19%). Secondary KLS (n = 18) patients were older and had more frequent and longer episodes, but had clinical symptoms and treatment responses similar to primary cases. In conclusion, KLS is a unique disease which may be more severe in female and secondary cases.

    View details for DOI 10.1093/brain/awh620

    View details for Web of Science ID 000233667500004

    View details for PubMedID 16230322

  • Temporal dynamics of late-night photic stimulation of the human circadian timing system AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Zeitzer, J. M., Khalsa, S. B., Boivin, D. B., Duffy, J. F., Shanahan, T. L., Kronauer, R. E., Czeisler, C. A. 2005; 289 (3): R839-R844


    The light-dark cycle is the primary synchronizing factor that keeps the internal circadian pacemaker appropriately aligned with the environmental 24-h day. Although it is known that ocular light exposure can effectively shift the human circadian pacemaker and do so in an intensity-dependent manner, the curve that describes the relationship between light intensity and pacemaker response has not been fully characterized for light exposure in the late biological night. We exposed subjects to 3 consecutive days of 5 h of experimental light, centered 1.5 h after the timing of the fitted minimum of core body temperature, and show that such light can phase advance shift the human circadian pacemaker in an intensity-dependent manner, with a logistic model best describing the relationship between light intensity and phase shift. A similar sigmoidal relationship is also observed between light intensity and the suppression of plasma melatonin concentrations that occurs during the experimental light exposure. As with a simpler, 1-day light exposure during the early biological night, our data indicate that the human circadian pacemaker is highly sensitive even to typical room light intensities during the late biological night, with approximately 100 lux evoking half of the effects observed with light 10 times as bright.

    View details for DOI 10.1152/ajpregu.00232.2005

    View details for Web of Science ID 000231243700026

    View details for PubMedID 15890792

  • Bilateral oculosympathetic paresis associated with loss of nocturnal melatonin secretion in patients with spinal cord injury JOURNAL OF SPINAL CORD MEDICINE Zeitzer, J. M., Ayas, N. T., Wu, A. D., Czeisler, C. A., Brown, R. 2005; 28 (1): 55-59


    Lesions along the sympathetic pathway to the eye produce oculosympathetic paresis (OSP, Horner's syndrome). The oculosympathetic pathway descends from the hypothalamus through the cervical spinal cord and ascends to the superior cervical ganglion (SCG), which innervates sympathetic targets in the ipsilateral face and eye. This pathway appears to closely co-localize with a similar retino-pineal neural pathway from the hypothalamus through the cervical spinal cord and SCG to the pineal gland. As such, lesions along this shared pathway, such as occur in neurologically complete injury to the cervical spinal cord (tetraplegia), would be predicted to result in simultaneous OSP and loss of pineal melatonin production. Loss of melatonin production may contribute to the pervasive sleep disruption observed in patients with tetraplegia.We assessed the presence of OSP by photographic documentation of ptosis and pupillary dilation response to cocaine eye drops in 5 individuals with neurologically complete damage to their upper thoracic or lower cervical spinal cord. We correlated these results with an analysis of the pattern of melatonin production in these same individuals.Bilateral OSP was present in individuals with cervical spinal cord injury; each also lacked significant production of melatonin. No evidence of OSP was observed in the 2 individuals with thoracic spinal cord injury below the level of the oculosympathetic pathway. Both had normal circadian rhythms of melatonin production, with timing and amplitude of the rhythm within normal parameters.The presence of bilateral oculosympathetic paresis can be predictive of the complete loss of the nocturnal production of melatonin.

    View details for Web of Science ID 000234835600012

    View details for PubMedID 15832904

  • Lesions of the suprachiasmatic nucleus eliminate the daily rhythm of hypocretin-1 release SLEEP Zhang, S. W., Zeitzer, J. M., Yoshida, Y., Wisor, J. P., Nishino, S., Edgar, D. M., Mignot, E. 2004; 27 (4): 619-627


    Hypocretins (orexins) are involved in the sleep disorder narcolepsy. While hypocretin-1 has a daily oscillation, little is known regarding the relative contribution of circadian and homeostatic components on hypocretin release. The effect of lesions of the suprachiasmatic nucleus (SCN) on hypocretin-1 in the cerebrospinal fluid (CSF) was examined.SCN-ablated (SCNx) and sham-operated control rats were implanted with activity-temperature transmitters. Animals were housed individually under 1 of 3 lighting conditions: 12-hour:12-hour light:dark cycle (LD), constant light (LL), and constant darkness (DD). Lesions were verified histologically and shown not to affect hypocretin-containing cells. Hypocretin-1 concentrations in the CSF were determined every 4 hours using radioimmunoassays.Control animals displayed robust circadian (LL, DD) and diurnal (LD) fluctuations in CSF hypocretin-1, locomotor activity, and temperature. Peak CSF hypocretin-1 was at the end of the active period. Activity, temperature, and CSF hypocretin-1 were arrhythmic in SCNx animals in LL and DD. In LD, a weak but significant fluctuation in activity and temperature but not CSF hypocretin-1 was observed in SCNx animals. We also explored correlations between CSF hypocretin-1, CSF corticosterone, and locomotor activity occurring prior to CSF sampling in arrhythmic SCNx rats under constant conditions. Significant correlations between hypocretin-1 and activity were observed both across and within animals, suggesting that interindividual and time-of-the-day differences in activity have significant effects on hypocretin release in arrhythmic animals. No correlation was found between CSF hypocretin-1 and corticosterone.Hypocretin-1 release is under SCN control. Locomotor activity influences the activity of the hypocretin neurons.

    View details for Web of Science ID 000223169300007

    View details for PubMedID 15282996

  • Locomotor-dependent and -independent components to hypocretin-1 (orexinA) regulation in sleep-wake consolidating monkeys JOURNAL OF PHYSIOLOGY-LONDON Zeitzer, J. M., Buckmaster, C. L., Lyons, D. M., Mignot, E. 2004; 557 (3): 1045-1053


    The hypocretin system is involved in the integration of hypothalamic functions with sleep and wake. Hypocretin-1 release peaks at the end of the active period in both diurnal and nocturnal species. A role for hypocretin-1 in the generation of locomotor activity has been suggested by electrophysiological and neurochemical studies in rodents, dogs and cats. These species, however, do not consolidate wake into a single, daily bout and manipulations of locomotion elicit changes in wakefulness, making it difficult to parse the relative contribution of these two factors. We have examined the relationship between locomotion and hypocretin-1 in a wake-consolidating animal, the squirrel monkey (Saimiri sciureus). Strikingly, we found that restricting locomotion to 17% of usual activity had no significant effect on the normal diurnal rise in cerebrospinal fluid (CSF) hypocretin-1, despite an associated increase in CSF cortisol. Increasing locomotion to greater than baseline activity did not significantly increase CSF hypocretin-1 concentrations, but did appear to have a positive modulatory effect on CSF hypocretin-1. In this wake-consolidating animal, locomotion is not necessary for CSF hypocretin-1 to increase throughout the daytime, but high levels of locomotion are likely to provide a small positive feedback onto the hypocretin system.

    View details for DOI 10.1113/jphysiol.2004.061606

    View details for Web of Science ID 000222403700029

    View details for PubMedID 15107479

  • Diurnal variation of cerebrospinal fluid hypocretin-1 (orexin-A) levels in control and depressed subjects 16th Annual Meeting of the Associated-Professional-Sleep-Societies Salomon, R. M., Ripley, B., Kennedy, J. S., Johnson, B., Schmidt, D., Zeitzer, J. M., Nishino, S., Mignot, E. ELSEVIER SCIENCE INC. 2003: 96–104


    Hypocretins, excitatory neuropeptides at monoaminergic synapses, appear to regulate human sleep-wake cycles. Undetectable cerebrospinal fluid hypocretin-1 levels are seen in narcolepsy, which is frequently associated with secondary depression. Shortened rapid eye movement latency is observed in both narcolepsy and depression. Cerebrospinal fluid hypocretin-1 levels have not been reported in mood disorders.We examined hypocretin-1 levels in 14 control and 15 depressed subjects. Cerebrospinal fluid was drawn continuously in supine subjects for 24 hours with an indwelling intrathecal catheter under entrained light-dark conditions. Depressed subjects were studied before and after 5 weeks of sertraline (n=10, three nonresponders) or bupropion (n=5, two nonresponders).Hypocretin-1 levels varied slightly (amplitude 10%) but significantly across the diurnal cycle in control subjects, with amplitude significantly reduced in depression (3%). Levels were lowest at midday, surprising for a hypothetically wake-promoting peptide. Mean hypocretin levels trended higher in depressive than in control subjects. Hypocretin-1 levels decreased modestly but significantly after sertraline (-14%) but not bupropion.Our results are consistent with previous physiologic findings in depression indicating dampened diurnal variations in hypocretin-1. The finding that sertraline but not bupropion slightly decreased cerebrospinal fluid hypocretin-1 indicates a serotoninergic influence on hypocretin tone.

    View details for DOI 10.1016/S0006-3223(03)01740-7

    View details for Web of Science ID 000184213800002

    View details for PubMedID 12873798

  • Circadian and homeostatic regulation of hypocretin in a primate model: Implications for the consolidation of wakefulness JOURNAL OF NEUROSCIENCE Zeitzer, J. M., Buckmaster, C. L., Parker, K. J., Hauck, C. M., Lyons, D. M., Mignot, E. 2003; 23 (8): 3555-3560


    In humans, consolidation of wakefulness into a single episode can be modeled as the interaction of two processes, a homeostatic "hour-glass" wake signal that declines throughout the daytime and a circadian wake-promoting signal that peaks in the evening. Hypocretins, novel hypothalamic neuropeptides that are dysfunctional in the sleep disorder narcolepsy, may be involved in the expression of the circadian wake-promoting signal. Hypocretins (orexins) are wake-promoting peptides, but their role in normal human sleep physiology has yet to be determined. We examined the daily temporal pattern of hypocretin-1 in the cisternal CSF of the squirrel monkey, a New World primate with a pattern of wake similar to that of humans. Hypocretin-1 levels peaked in the latter third of the day, consistent with the premise that hypocretin-1 is involved in wake regulation. When we lengthened the wake period by 4 hr, hypocretin-1 concentrations remained elevated, indicating a circadian-independent component to hypocretin-1 regulation. Changes in the stress hormone cortisol were not correlated with hypocretin-1 changes. Although hypocretin-1 is at least partially activated by a reactive homeostatic mechanism, it is likely also regulated by the circadian pacemaker. In the squirrel monkey, hypocretin-1 works in opposition to the accumulating sleep drive during the day to maintain a constant level of wake.

    View details for Web of Science ID 000182475200052

    View details for PubMedID 12716965

  • Regional analyses of CNS microdialysate glucose and lactate in seizure patients EPILEPSIA Cornford, E. M., Shamsa, K., Zeitzer, J. M., Enriquez, C. M., Wilson, C. L., Behnke, E. J., Fried, I., Engel, J. 2002; 43 (11): 1360-1371


    To correlate glucose (and lactate) results obtained from microdialysate to recent studies suggesting that glucose transporter activity may be significantly altered in seizures.We used a fluorometric technique to quantify glucose and lactate levels in microdialysates collected from two to four depth electrodes implanted per patient in the temporal and frontal lobes of a series of four patients. Hour-by-hour and day-to-day changes in brain glucose and lactate levels at the same site were recorded. Additionally we compared regional variations in lactate/glucose ratios around the predicted epileptogenic region.Lactate/glucose ratios in the range of 1-2:1 were the most commonly seen. When the lactate/glucose ratio was <1:1, we typically observed a relative increase in local glucose concentration (rather than decreased lactate), suggesting increased transport, perhaps without increased glycolysis. In some sites, lactate/glucose ratios of 3:1-15:1 were seen, suggesting that a circumscribed zone of inhibition of tricarboxylic acid cycle activity may have been locally induced. In these dialysates, collected from probes closer to the epileptogenic region, the large increase in lactate/glucose ratios was a result of both increased lactate and reduced glucose levels.We conclude that regional variations in brain extracellular glucose concentrations may be of greater magnitude than previously believed and become even more accentuated in partial seizure patients. Data from concomitant assays of microdialysate lactate and glucose may aid in understanding cerebral metabolism.

    View details for Web of Science ID 000179307900011

    View details for PubMedID 12423386

  • Ultradian sleep-cycle variation of serotonin in the human lateral ventricle NEUROLOGY Zeitzer, J. M., Maidment, N. T., Behnke, E. J., Ackerson, L. C., Fried, I., Engel, J., Wilson, C. L. 2002; 59 (8): 1272-1274


    Serotonin is thought to be intimately involved in the regulation of sleep and waking in humans, though the evidence for such is indirect. Using in vivo microdialysis, the authors show that serotonin in human ventricular CSF covaries with the state of consciousness. They hypothesize that CSF serotonin may be acting in an endocrine-like manner through activation of known leptomeningeal serotonin receptors and possibly participating in modulation of choroidal production of CSF.

    View details for Web of Science ID 000178726700033

    View details for PubMedID 12391366

  • Diurnal variation of CSF hypocretin-1 (orexin A) levels in control and depressed subjects Salomon, R. M., Ripley, B., Kennedy, J. S., Schmidt, D., Zeitzer, J., Nishino, S., Mignot, E. AMER ACAD SLEEP MEDICINE. 2002: A12–A13
  • Peak of circadian melatonin rhythm occurs later within the sleep of older subjects AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM Duffy, J. F., Zeitzer, J. M., Rimmer, D. W., Klerman, E. B., Dijk, D. J., Czeisler, C. A. 2002; 282 (2): E297-E303


    We investigated the relationship between sleep timing and the timing of the circadian rhythm of plasma melatonin secretion in a group of healthy young and older subjects without sleep complaints. The timing of sleep and the phase of the circadian melatonin rhythm were earlier in the older subjects. The relationship between the plasma melatonin rhythm and the timing of sleep was such that the older subjects were sleeping and waking earlier relative to their nightly melatonin secretory episode. Consequently, the older subjects were waking at a time when they had higher relative melatonin levels, in contrast with younger subjects, whose melatonin levels were relatively lower by wake time. Our findings indicate that aging is associated not only with an advance of sleep timing and the timing of circadian rhythms but also with a change in the internal phase relationship between the sleep-wake cycle and the output of the circadian pacemaker. In healthy older subjects, the relative timing of the melatonin rhythm with respect to sleep may not play a causal role in sleep disruption.

    View details for Web of Science ID 000173460600007

    View details for PubMedID 11788360

  • The role of hypocretins (orexins) in sleep regulation and narcolepsy ANNUAL REVIEW OF NEUROSCIENCE Taheri, S., Zeitzer, J. M., Mignot, E. 2002; 25: 283-313


    The hypocretins (orexins) are two novel neuropeptides (Hcrt-1 and Hcrt-2), derived from the same precursor gene, that are synthesized by neurons located exclusively in the lateral, posterior, and perifornical hypothalamus. Hypocretin-containing neurons have widespread projections throughout the CNS with particularly dense excitatory projections to monoaminergic centers such as the noradrenergic locus coeruleus, histaminergic tuberomammillary nucleus, serotoninergic raphe nucleus, and dopaminergic ventral tegmental area. The hypocretins were originally believed to be primarily important in the regulation of appetite; however, a major function emerging from research on these neuropeptides is the regulation of sleep and wakefulness. Deficiency in hypocretin neurotransmission results in the sleep disorder narcolepsy in mice, dogs, and humans. The hypocretins are also uniquely positioned to link sleep, appetite, and neuroendocrine control. The aim of this review is to describe and discuss the current knowledge regarding the hypocretin neurotransmitter system in narcolepsy and normal sleep.

    View details for DOI 10.1146/annurev.neuro.25.112701.142826

    View details for Web of Science ID 000177354800009

    View details for PubMedID 12052911

  • Absence of an increase in the duration of the circadian melatonin secretory episode in totally blind human subjects JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Klerman, E. B., Zeitzer, J. M., Duffy, J. F., Khalsa, S. B., Czeisler, C. A. 2001; 86 (7): 3166-3170


    The daily rhythm of melatonin influences multiple physiological measures, including sleep tendency, circadian rhythms, and reproductive function in seasonally breeding mammals. The biological signal for photoperiodic changes in seasonally breeding mammals is a change in the duration of melatonin secretion, which in a natural environment reflects the different durations of daylight across the year, with longer nights leading to a longer duration of melatonin secretion. These seasonal changes in the duration of melatonin secretion do not simply reflect the known acute suppression of melatonin secretion by ocular light exposure, but also represent long-term changes in the endogenous nocturnal melatonin episode that persist in constant conditions. As the eyes of totally blind individuals do not transmit ocular light information, we hypothesized that the duration of the melatonin secretory episode in blind subjects would be longer than those in sighted individuals, who are exposed to light for all their waking hours in an urban environment. We assessed the melatonin secretory profile during constant posture, dim light conditions in 17 blind and 157 sighted adults, all of whom were healthy and using no prescription or nonprescription medications. The duration of melatonin secretion was not significantly different between blind and sighted individuals. Healthy blind individuals after years without ocular light exposure do not have a longer duration of melatonin secretion than healthy sighted individuals.

    View details for Web of Science ID 000169838300042

    View details for PubMedID 11443183

  • Fluctuations in neurotransmitter concentrations in human brain dialysates during sleep or wakefulness, during epileptic seizures or following cognitive challenge 9th International Conference on In Vivo Methods Maidment, N. T., Fried, I., LOPEZ, F., Zeitzer, J. M., Behnke, E. B., Ackerson, L. C., Engel, J., Wilson, C. L. UNIV COLLEGE DUBLIN. 2001: 160–161
  • Dose-response relationship for light intensity and ocular and electroencephalographic correlates of human alertness BEHAVIOURAL BRAIN RESEARCH Cajochen, C., Zeitzer, J. M., Czeisler, C. A., Dijk, D. J. 2000; 115 (1): 75-83


    Light can elicit both circadian and acute physiological responses in humans. In a dose response protocol men and women were exposed to illuminances ranging from 3 to 9100 lux for 6.5 h during the early biological night after they had been exposed to <3 lux for several hours. Light exerted an acute alerting response as assessed by a reduction in the incidence of slow-eye movements, a reduction of EEG activity in the theta-alpha frequencies (power density in the 5-9 Hz range) as well as a reduction in self-reported sleepiness. This alerting response was positively correlated with the degree of melatonin suppression by light. In accordance with the dose response function for circadian resetting and melatonin suppression, the responses of all three indices of alertness to variations in illuminance were consistent with a logistic dose response curve. Half of the maximum alerting response to bright light of 9100 lux was obtained with room light of approximately 100 lux. This sensitivity to light indicates that variations in illuminance within the range of typical, ambient, room light (90-180 lux) can have a significant impact on subjective alertness and its electrophysiologic concomitants in humans during the early biological night.

    View details for Web of Science ID 000089374500009

    View details for PubMedID 10996410

  • Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression JOURNAL OF PHYSIOLOGY-LONDON Zeitzer, J. M., Dijk, D. J., Kronauer, R. E., Brown, E. N., Czeisler, C. A. 2000; 526 (3): 695-702


    Ocular exposure to early morning room light can significantly advance the timing of the human circadian pacemaker. The resetting response to such light has a non-linear relationship to illuminance. The dose-response relationship of the human circadian pacemaker to late evening light of dim to moderate intensity has not been well established. Twenty-three healthy young male and female volunteers took part in a 9 day protocol in which a single experimental light exposure6.5 h in duration was given in the early biological night. The effects of the light exposure on the endogenous circadian phase of the melatonin rhythm and the acute effects of the light exposure on plasma melatonin concentration were calculated. We demonstrate that humans are highly responsive to the phase-delaying effects of light during the early biological night and that both the phase resetting response to light and the acute suppressive effects of light on plasma melatonin follow a logistic dose-response curve, as do many circadian responses to light in mammals. Contrary to expectations, we found that half of the maximal phase-delaying response achieved in response to a single episode of evening bright light ( approximately 9000 lux (lx)) can be obtained with just over 1 % of this light (dim room light of approximately 100 lx). The same held true for the acute suppressive effects of light on plasma melatonin concentrations. This indicates that even small changes in ordinary light exposure during the late evening hours can significantly affect both plasma melatonin concentrations and the entrained phase of the human circadian pacemaker.

    View details for Web of Science ID 000089202500022

    View details for PubMedID 10922269

  • Absence of detectable melatonin and preservation of cortisol and thyrotropin rhythms in tetraplegia JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Zeitzer, J. M., Ayas, N. T., Shea, S. A., Brown, R., Czeisler, C. A. 2000; 85 (6): 2189-2196


    The human circadian timing system regulates the temporal organization of several endocrine functions, including the production of melatonin (via a neural pathway that includes the spinal cord), TSH, and cortisol. In traumatic spinal cord injury, afferent and efferent circuits that influence the basal production of these hormones may be disrupted. We studied five subjects with chronic spinal cord injury (three tetraplegic and two paraplegic, all neurologically complete injuries) under stringent conditions in which the underlying circadian rhythmicity of these hormones could be examined. Melatonin production was absent in the three tetraplegic subjects with injury to their lower cervical spinal cord and was of normal amplitude and timing in the two paraplegic subjects with injury to their upper thoracic spinal cord. The amplitude and the timing of TSH and cortisol rhythms were robust in the paraplegics and in the tetraplegics. Our results indicate that neurologically complete cervical spinal injury results in the complete loss of pineal melatonin production and that neither the loss of melatonin nor the loss of spinal afferent information disrupts the rhythmicity of cortisol or TSH secretion.

    View details for Web of Science ID 000088460500023

    View details for PubMedID 10852451

  • Do plasma melatonin concentrations decline with age? AMERICAN JOURNAL OF MEDICINE Zeitzer, J. M., Daniels, J. E., Duffy, J. F., Klerman, E. B., Shanahan, T. L., Dijk, D. J., Czeisler, C. A. 1999; 107 (5): 432-436


    Numerous reports that secretion of the putative sleep-promoting hormone melatonin declines with age have led to suggestions that melatonin replacement therapy be used to treat sleep problems in older patients. We sought to reassess whether the endogenous circadian rhythm of plasma melatonin concentration changes with age in healthy drug-free adults.We analyzed the amplitude of plasma melatonin profiles during a constant routine in 34 healthy drug-free older subjects (20 women and 14 men, aged 65 to 81 years) and compared them with 98 healthy drug-free young men (aged 18 to 30 years).We could detect no significant difference between a healthy and drug-free group of older men and women as compared to one of young men in the endogenous circadian amplitude of the plasma melatonin rhythm, as described by mean 24-hour average melatonin concentration (70 pmol/liter vs 73 pmol/liter, P = 0.97), or the duration (9.3 hours vs 9.1 hours, P = 0.43), mean (162 pmol/liter vs 161 pmol/liter, P = 0.63), or integrated area (85,800 pmol x min/liter vs 86,700 pmol x min/liter, P = 0.66) of the nocturnal peak of plasma melatonin.These results do not support the hypothesis that reduction of plasma melatonin concentration is a general characteristic of healthy aging. Should melatonin replacement therapy or melatonin supplementation prove to be clinically useful, we recommend that an assessment of endogenous melatonin be carried out before such treatment is used in older patients.

    View details for Web of Science ID 000083583900004

    View details for PubMedID 10569297

  • Resetting the melatonin rhythm with light in humans JOURNAL OF BIOLOGICAL RHYTHMS Shanahan, T. L., Zeitzer, J. M., Czeisler, C. A. 1997; 12 (6): 556-567


    The endogenous circadian rhythm of melatonin in humans provides information regarding the resetting response of the human circadian timing system to changes in the light-dark (LD) cycle. Alterations in the LD cycle have both acute and chronic effects on the observed melatonin rhythm. Investigations to date have firmly established that the melatonin rhythm can be reentrained following an inversion of the LD cycle. Exposure to bright light and darkness given over a series of days can rapidly induce large-magnitude phase shifts of the melatonin rhythm. Even single pulses of bright light can shift the timing of the melatonin rhythm. Recent data have demonstrated that lower light intensities than originally believed are capable of resetting the melatonin rhythm and that stimulation of photopically sensitive photoreceptors (i.e., cones) is sufficient to reset the endogenous circadian melatonin rhythm. In addition to phase resetting, exposure to light of critical timing, strength, and duration can attenuate the amplitude of the endogenous circadian rhythm of melatonin. Measurement of melatonin throughout resetting trials provides a dynamic view of the resetting response of the human circadian pacemaker to light. Future studies of the melatonin rhythm in humans may further characterize the resetting response of the human circadian timing system to light.

    View details for Web of Science ID A1997YJ44900010

    View details for PubMedID 9406030

  • Photopic transduction implicated in human circadian entrainment NEUROSCIENCE LETTERS Zeitzer, J. M., Kronauer, R. E., Czeisler, C. A. 1997; 232 (3): 135-138


    Despite the preeminence of light as the synchronizer of the circadian timing system, the phototransductive machinery in mammals which transmits photic information from the retina to the hypothalamic circadian pacemaker remains largely undefined. To determine the class of photopigments which this phototransductive system uses, we exposed a group (n = 7) of human subjects to red light below the sensitivity threshold of a scotopic (i.e. rhodopsin/rod-based) system, yet of sufficient strength to activate a photopic (i.e. cone-based) system. Exposure to this light stimulus was sufficient to reset significantly the human circadian pacemaker, indicating that the cone pigments which mediate color vision can also mediate circadian vision.

    View details for Web of Science ID A1997XV84100004

    View details for PubMedID 9310298